Regulation of K+ Nutrition in Plants

Frontiers in Plant Science | www.frontiersin.org 1 March 2019 | Volume 10 | Article 281 REVIEW published: 20 March 2019 doi: 10.3389/fpls.2019.00281 Edited by: Lam-Son Tran, RIKEN, Japan Reviewed by: Manuel Nieves-Cordones, Center for Edaphology and Applied Biology of Segura, Spanish National Research Council (CSIC), Spain Fernando Aleman, The Scripps Research Institute, UnitedStates *Correspondence: José M. Pardo [email protected] Specialty section: This article was submitted to Plant Abiotic Stress, a section of the journal Frontiers in Plant Science Received: 07 December 2018 Accepted: 20 February 2019 Published: 20 March 2019 Citation: Ragel P, Raddatz N, Leidi EO, Quintero FJ and Pardo JM (2019) Regulation of K+ Nutrition in Plants. Front. Plant Sci. 10:281. doi: 10.3389/fpls.2019.00281 Regulation of K+ Nutrition in Plants PaulaRagel1,2, NataliaRaddatz1, EduardoO.Leidi3, FranciscoJ.Quintero1 and JoséM.Pardo1* 1 Instituto de Bioquímica Vegetal y Fotosíntesis, Consejo Superior de Investigaciones Científicas y Universidad de Sevilla, Seville, Spain, 2 Centre for Organismal Studies, Universität Heidelberg, Heidelberg, Germany, 3 Instituto de Recursos Naturales y Agrobiologia de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain Modern agriculture relies on mineral fertilization. Unlike other major macronutrients, potassium (K+) is not incorporated into organic matter but remains as soluble ion in the cell sap contributing up to 10% of the dry organic matter. Consequently, K+ constitutes a chief osmoticum to drive cellular expansion and organ movements, such as stomata aperture. Moreover, K+ transport is critical for the control of cytoplasmic and luminal pH in endosomes, regulation of membrane potential, and enzyme activity. Not surprisingly, plants have evolved a large ensemble of K+ transporters with defined functions in nutrient uptake by roots, storage in vacuoles, and ion translocation between tissues and organs. This review describes critical transport proteins governing K+ nutrition, their regulation, and coordinated activity, and summarizes our current understanding of signaling pathways activated by K+ starvation. Keywords: plant nutrition, potassium, nitrate, regulation, long-distance transport INTRODUCTION Potassium (K+) is of paramount importance in plant cell physiology. K+ is an essential macronutrient that fulfills critical functions related to enzyme activation, osmotic adjustment, turgor generation, cell expansion, regulation of membrane electric potential, and pH homeostasis (Hawkesford et al., 2012). While the K+ concentration in the soil solution may vary widely from 0.01 to 20 mM, plant cells maintain a relatively constant concentration of 80–100 mM in the cytoplasm (Rodriguez-Navarro, 2000). Moreover, plants accumulate large amounts of K+ in their vacuoles, surpassing purely nutritional requirements. Hence, K+ is the most abundant cation in plant cells, comprising up to 10% of plant dry weight and often exceeding the ca. 2% that supports near-maximal growth rates (White and Karley, 2010). There is a steep curvilinear relationship between the tissue concentration of K+ and plant growth, from which a critical concentration of K+ supporting 90% of maximum yield can be determined. Above this concentration, growth has no correlation with the increased K+ content, but at lower K+ concentrations, growth declines rapidly. Consequently, K+ fertilization is common practice in modern agriculture and about 40–60% of crop yields are attributable to commercial fertilizer use (Stewart et al., 2005). However, agricultural fertilization is far from being fine-tuned with nutritional requirements. K+ is taken up from the soil solution by root epidermal and cortical cells. Once K+ is inside the root symplast, it may be stored in vacuoles, where it fulfills osmotic functions, or is transported to the shoot via xylem (Pardo and Rubio, 2011). In turn, shoot cells may also supply stored K+ for redistribution via phloem. In this transit from the soil to the different Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 2 March 2019 | Volume 10 | Article 281 plant organs, K+ crosses various cell membranes through K+- specific transport systems (Figure 1). Coordinated operation of the different transport systems within the plant to secure K+ uptake from the soil and delivery to the different plant organs requires complex K+ sensing and signaling mechanisms. Because of the extraordinary diversity of K+ transporters in plant cells and the physiological and developmental processes in which they are involved, this review is focused on the molecular mechanisms mediating K+ uptake and release at the plasma membrane level, with an emphasis on K+ absorption from the soil and distribution throughout the plant due to the relevance of these processes in plant nutrition. Storage of K+ into vacuoles is treated only briefly and readers are referred to other comprehensive reviews describing transport systems operating at the tonoplast (Martinoia et al., 2012; Ahmad and Maathuis, 2014; Eisenach and De Angeli, 2017; Martinoia, 2018). Last, because of the extensive interactions of nitrogen and K+ in plant mineral nutrition, wesummarize the coordinated regulation of NO3− and K+ uptake and long-distance transport in Arabidopsis. Uptake and distribution of K+ in plant cells is carried out by a variety of transporter proteins categorized into several families with varied structures and transport mechanisms that comprise the channel families Shaker-like voltage-dependent, the tandem-pore (TPK), and the two-pore channels (TPC) (Hedrich, 2012), the carrier-like families KT/HAK/KUP (NievesCordones et al., 2014a; Li et al., 2018), HKT uniporters and symporters (Hamamoto etal., 2015), and cation-proton antiporters (CPA). The CPA family is the largest one and includes the NHX, CHX, and KEA antiporters (Sze and Chanroj, 2018). In this review, we describe the structure and diversity of the main K+ transporter families whose members contribute substantially to K+ nutrition. Other proteins with uncertain roles or descriptions of transport activities without candidate proteins have been omitted. TRANSPORT PROTEIN FAMILIES INVOLVED IN K+ NUTRITION K+-Selective Channels The first K+ transporter with a role in nutrient uptake was the Shaker-like, voltage-gated, and K+-selective channel AKT1 (Hirsch et al., 1998). Although voltage-gated (VG) channels of plants are phylogenetically related to animal Shaker channels, they are distinct and include additional functional domains (Jegla et al., 2018). The basic architecture of VG channels consists of four α-subunits surrounding a central aqueous pore for K+ permeation. Each subunit contains six transmembrane segments, named S1–S6, which can bedivided into two different modules: the first four α-helices form a voltage-sensor domain that contains multiple positively charged residues that moves within the membrane in response to voltage. This movement is directly coupled to the opening or closing of the channel. The segments S5, S6, and the pore loop, form the pore domain, named P, where each of the four subunits contributes equally to the permeation pathway. Moreover, plant α-subunits have a long C-terminal region constituting more than half of the protein (Figure 2). This cytosolic tail includes several functional domains: (1) a linker region (C-linker) proximal to the pore FIGURE 1 | Transporters involved in K+ uptake by roots and inter-organ partition. HAK5, AKT1, and non-selective cyclic nucleotide-gated cation channels (CNGC) all contribute to K+ nutrition, albeit at different ranges of substrate concentrations, from lowto high-availability, respectively. K+ efflux through the outward-rectifying GORK channel facilitates the fine-tuning of plasma membrane electrical potential, and allows repolarization under circumstances that promote depolarization, such as salinity stress. In the root stele, the outward-rectifying SKOR channel releases K+ into the xylem vessels for nutrient delivery to the shoots. The nitrate transporter NRT1.5 facilitates K+ uploading into the xylem either by electrical coupling with other K+-selective transporters or directly acting as K+/H+ antiporter. In aerial tissues, an array of K+-influx channels and KT/HAK/KUP carriers allow the uptake of the incoming K+ into green cells. K+ is stored inside vacuoles by NHX exchangers and released back to the cytosol by TPK and TPC1 channels, and possibly also by KT/HAK/KUP carriers at the tonoplast (the vacuole in root cells is omitted for simplicity). The plasma membrane outward K+ channel AKT2 releases K+ into the phloem for returning K+ to the root and to facilitate the uploading of photosynthates into the phloem sap. Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 3 March 2019 | Volume 10 | Article 281 that transduces conformational changes that gate the channel and that may also determine the target membrane (NievesCordones et al., 2014b; Jegla et al., 2018); (2) a conserved and essential cyclic nucleotide-binding homology domain (CNBHD) whose function is not the binding of cNMP but to mediate the interactions between subunits within the channel tetramer; (3) an ankyrin domain (found in only six out of the nine Arabidopsis VG channels), which may mediate the binding of interacting proteins (Michaely and Bennett, 1992); and (4) a distal KT/KHA domain rich in hydrophobic and acidic residues, that is unique to plant K+ channels, and is involved in channel tetramerization and clustering at the membrane (Daram et al., 1997; Ehrhardt et al., 1997; Zimmermann et al., 2001; Dreyer et al., 2004). Plant voltage-gated K+ channels are divided into three subfamilies regarding their response to the membrane potential (Dreyer and Uozumi, 2011): (1) Inward-rectifying (Kin) channels that in Arabidopsis include AKT1, AKT6, KAT1, and KAT2; they open at hyperpolarized membrane potentials allowing the uptake of K+. (2) Outward-rectifying (Kout) channels that mediate K+ release because they open at depolarized membrane potentials; this group is composed of SKOR and GORK channels. (3) Weakly rectifying (Kweak) channels that can mediate both K+ uptake and release, and whose Arabidopsis representative is AKT2. In addition, the Arabidopsis KC1 (KAT3) is an electrically silent Shaker-like protein that interacts with and regulates functionality of the Kin channels AKT1, KAT1, KAT2, and AKT2, but not the Kout channels (Jeanguenin etal., 2011). This interaction negatively shifts the activation threshold of Kin channels and decreases the macroscopic inward conductance compared to that of homomeric channels (Dreyer etal., 1997; Duby et al., 2008; Geiger et al., 2009). Heteromerization of different subunits of Kin channels is of great importance to increase the functional diversity and regulation of different cell types (Dreyer etal., 1997; Véry and Sentenac, 2003; Xicluna et al., 2007; Jeanguenin et al., 2008; Lebaudy et al., 2008; Lebaudy et al., 2010). Although this behavior has also been suggested for outward-rectifier (Kout) channels, heteromerization has been reported only among subunits of Kin or Kout, preventing formation of heteromeric structures between the two subunit types (Dreyer et al., 2004). K+-Uptake Carriers Proteins of the KT/HAK/KUP family are present in plants, fungi, bacteria, and even viruses (Greiner et al., 2011; SantaMaria et al., 2018), and they are often associated with K+ transport across membranes and K+ supply. In bacterial genomes, K+ carriers of this family are encoded by single-copy genes named kup. In Escherichia coli, kup is a constitutive low-affinity uptake system that operates as K+-H+ symporter (Zakharyan and Trchounian, 2001). In fungi, the homologous proteins are encoded by HAK1-like genes present as oneor two-copy in AB C FIGURE 2 | Topological models of the main ion transporters involved in K+ nutrition. (A) Voltage-gated K+ channels contain six transmembrane domains (S1–S6); S4 is the voltage-sensor characterized by the array of positively charged amino acids (+). The long C-terminal tail contains several conserved domains: C-linker, a cyclic nucleotide binding homologous domain (CNBHD), an ankyrin domain (ANK), and a final region rich in hydrophobic and acidic residues (KHA). (B) HKT transporters have a channel-like structure that contains four identical subunits (a–d), each comprising two transmembrane helices (M1 and M2) connected by the P-loop involved in ion selectivity. (C) KT/HAK/KUP transporters have 12 putative transmembrane domains (TMs). TM1-5 and TM6-10 are predicted to fold in the same conformation but showing inverse symmetry. Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 4 March 2019 | Volume 10 | Article 281 most species. In contrast to bacterial kup, fungal HAK genes are strongly induced by K+ starvation and the encoded proteins mediate high-affinity K+ transport (Benito et al., 2011). In plants, these transporters are known as KT, HAK, or KUP (KT/HAK/KUP family) and they are represented by multiple genes in their genomes. Members of this family have been widely associated with high-affinity K+ uptake from the soil, while others may function in both low-affinity and/or highaffinity transport (Luan et al., 2009; Very et al., 2014) and other roles related, for example, to K+ translocation, control of water movement at the plant level, salt tolerance, osmotic/ drought responses, transport of other alkali cations, and developmental processes in plants, such as root hair growth and auxin distribution (Li etal., 2018; Santa-Maria etal., 2018). These diverse functions of KT/HAK/KUP transporters may all result from their critical roles in cellular K+ homeostasis. KT/HAK/KUP genes are not present in animal cells, what could indicate that they are crucial for K+ transport in organisms facing external solutions with fluctuating and very low K+ concentrations, often in the μM range (Ashley et al., 2006). Based on the present knowledge, KT/HAK/KUP genes are present in all plant genomes, which contrasts with that in the other kingdoms, where they are only present in certain species (Grabov, 2007; Greiner etal., 2011). This difference may reflect the importance of these transporters for the plant’s way of life. KT/HAK/KUP transporters of land plants are classified according to their sequence homology into six clusters or clades (I–VI), with clade VI including only members of bryophytes (Santa-Maria etal., 2018). Phylogenetic analysis shows that all KT/HAK/KUPs from algae diverge from land plant clades, suggesting that the diversification into these groups took place after the colonization of land by green organisms (Santa-Maria et al., 2018). The KT/HAK/KUP group from angiosperms displays a high and rather variable number of members in the different plant species genomes that have been sequenced so far. For instance, there are 13 genes in Arabidopsis, 16 in peach, 17 in grapevine, 20 in Medicago, 21 in Cassava, 27 in rice, maize, and Brachypodium, and 57 in Panicum virgatum (Song et al., 2015; Nieves-Cordones et al., 2016a,c; Ou et al., 2018). Members of KT/HAK/KUP family in angiosperm are classified among clades I–V (Nieves-Cordones et al., 2016c). The KT/HAK/KUP transporters involved in K+ uptake from the soil are clustered into a distinct subgroup of clade I, termed Ia (Nieves-Cordones et al., 2016c) and that we call herein HAK1-like transporters by analogy with the fungal counterparts. This subgroup includes barley HvHAK1 (Santa-María et al., 1997; Gierth and Mäser, 2007), Arabidopsis AtHAK5 (Rubio et al., 2000; Gierth et al., 2005), rice OsHAK1 and OsHAK5 (Bañuelos et al., 2002), pepper CaHAK1 (Martinez-Cordero et al., 2004), tomato LeHAK5 (Nieves-Cordones et al., 2007), and Thellungiella ThHAK5 (Alemán etal., 2009b). High-affinity K+ transport has been demonstrated for all the HAK1-like transporters in heterologous expression systems (Nieves-Cordones et al., 2014a). On the other hand, AtKUP7, belonging to clade V, could beinvolved in K+ uptake from low to moderate external K+ concentrations (Han etal., 2016), and thus the participation in K+ uptake from soil of proteins from different clades should not bediscarded. Interestingly, other members of clade Icould be related with K+ uptake by cells from specialized tissues. DmHAK5 from Venus flytraps is implicated in the uptake of K+ released from the digested prey in the bi-lobed capture organ (Scherzer etal., 2015), whereas the quinoa CqHAK5-like drives K+ influx into cells of the leaf salt bladders to contribute to the osmotic balance of the cytosol against the osmotic pressure of the salt-containing vacuoles (Bohm et al., 2018). KT/HAK/KUP transporters are phylogenetically related to the superfamily of acid-polyamine-organocation (APC) transporters that comprises secondary active transport proteins responsible for uniport, symport, and antiport of a wide range of substrates (Vastermark et al., 2014). Taking as template crystal structures of prokaryotic APC transporters, computational 3D modeling of AtKUP7 (Ahn etal., 2004; Al-Younis etal., 2015; Santa-Maria et al., 2018), AtKUP4/TRH1 (Daras et al., 2015), OsHAK1 (Rai etal., 2017), AtKUP1/TRH1 (Santa-Maria etal., 2018), AtHAK5 (Santa-Maria et al., 2018), and HvHAK1 (Santa-Maria et al., 2018) has been reported. The structural models (Figure 2) show the presence of common attributes among all of them: (1) a hydrophobic core containing 10–14 transmembrane (TM) segments; and (2) three cytosolic domains—the Nand C-termini and a region containing approximately 70 residues situated between second and third TMs (loop II–III). Although, the structure of the pore region has not been described yet, several works have analyzed the effect of mutations on the function of these transporters (Santa-Maria et al., 2018). So far, results indicated that several parts of the protein may contribute to setting the Vmax of the transporter and that the region including from N-terminus to loop II–III may contribute in determining its Km. Furthermore, sequence alignments show that, although there is not extensive sequence conservation, 40 amino acid residues are conserved in exactly the same position in all the eukaryotic HAK transporters and in the Kup bacterial transporters (Rodriguez-Navarro, 2000). Six of these conserved residues are included in a highly conserved motif in the first transmembrane domain whose consensus sequence is GVVYGDLGTSPLY (the amino acids conserved in all proteins are in bold) (Rodriguez-Navarro, 2000). A helical-wheel representation of this transmembrane fragment locates three glycine residues on the same side of the helix, which in the case of a tetrameric structure may operate as a substrate selectivity filter analogous to the GXGYGD motif highly conserved in K+ channels. Regarding this, it has been suggested that AtKUP4/TRH1 may form homodimers (Daras etal., 2015), likely involving the interaction between C-terminus domains and less likely between loops II–III. Contrary to VG channels that are all targeted to the plasma membrane, KT/HAK/KUP transporters have been reported in different subcellular compartments (Table 1). The majority of the characterized transporters of the KT/HAK/KUP family are located in the plasma membrane, although not all of them are involved in K+ nutrition. For instance, AtKUP4/TRH1 seems to participate in auxin transport related with root gravitropism and root hair development (Rigas etal., 2013), whereas AtKUP6 acts in lateral root initiation and development in the auxin and ABA crosstalk signaling pathways (Osakabe et al., 2013). Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 5 March 2019 | Volume 10 | Article 281 HKT Proteins The ample repertoire of transporters encoded in the genome of plants includes proteins that are collectively known as High affinity K+ Transporters (HKTs; Figure 2) despite the fact that these proteins facilitate Na+-selective uniport or Na+-K+ symport with a channel-like activity (Benito et al., 2014). Phylogenetic and functional analyses distinguished two HKT subfamilies (Platten et al., 2006). Members of subfamily I (HKT1) are ubiquitous in plants, Na+-selective, and mostly involved in Na+ recirculation through vascular tissues, as best exemplified by AtHKT1;1 (Sunarpi et al., 2005). Members of subfamily II (HKT2) have been found only in monocotyledonous species. Although they are all K+-permeable, mechanistically HKT2s can operate as either Na+-K+ symporters or K+-selective uniporters [reviewed by Benito etal. (2014)]. HKT2-like proteins of cereals have been involved in K+ nutrition. K+ UPTAKE BY ROOTS The uptake of K+ by roots (often measured with rubidium as tracer) exhibits a biphasic kinetics in response to increasing external concentrations corresponding to highand low-affinity transport systems, which work at low (<1 mM) and high (>1mM) external K+ concentrations respectively (Epstein etal., 1963; Gierth and Mäser, 2007). At high concentration in the soil solution, K+ crosses the membrane mostly through channels. The channels simply give a path for the ions allowing them to move down the electrochemical gradient. At low K+ concentration, active transporter systems are needed in order to pull K+ inside the cell against its electrochemical gradient. However, studies in several plant species have shown that channels may be involved in K+ uptake in the high-affinity range of K+ concentrations (Rubio et al., 2010) as long as the membrane is sufficiently hyperpolarized, i.e. highly electronegative inside (Hirsch et al., 1998; Spalding et al., 1999; Gierth and Mäser, 2007; Rubio et al., 2010). The sensitivity to NH4+ is an important characteristic of highaffinity K+ uptake mediated by carriers that has been used as a tool for the identification of additional high-affinity transport systems (Santa-María etal., 1997; Nieves-Cordones etal., 2007). NH4+-sensitive and -insensitive components of high-affinity K+ uptake have been identified in Arabidopsis (Spalding etal., 1999), barley (Santa-Maria et al., 2000), pepper (Martinez-Cordero et al., 2005), and rice (Bañuelos etal., 2002; Chen et al., 2015). Results indicate that the NH4+-sensitive component of K+ uptake is likely mediated by KT/HAK/KUP transporters (HAK1-like transporters), whereas inward-rectifier K+ channels (AKT1-like channels) constitute the NH4+-insensitive pathway (Santa-Maria etal., 2000; Nieves-Cordones etal., 2014a). Together, AKT1-like channels and HAK1-like transporters are now thought to constitute the main systems for K+ uptake in plants under low-K+ concentrations (Table 2). However, the NH4+-sensitive and -insensitive pathways appear to contribute differently to highaffinity K+ uptake depending on the plant species and the ionic external concentration of transported substrates, mainly K+, NH4+, and Na+ (Aleman et al., 2011; Nieves-Cordones et al., 2016c). Among the inward-rectifying K+ channels of Arabidopsis, only AKT1 and AtKC1 are abundantly expressed in root tissues (Reintanz etal., 2002). AtKC1 expressed alone remains in the endoplasmic reticulum, but it can be recruited to the plasma membrane to regulate AKT1 activity (Duby et al., 2008; Geiger et al., 2009; Honsbein et al., 2009; Wang et al., 2010). In addition, AKT1 is positively regulated by the protein kinase complex comprising the kinase CIPK23 and one of the two alternative calciumdependent regulatory subunits CBL1 and CBL9 (Li et al., 2006; TABLE 1 | Sub-cellular location of selected Arabidopsis, barley, rice, and Physcomitrella patens KT/HAK/KUP transporters. Transporter/location Plasma membrane Tonoplast ER-like membranes Thylakoid membranes References AtHAK5 √Qi etal., 2008 AtKUP4/TRH1 √√√ Rigas etal., 2013 AtKUP5 √Jaquinod etal., 2007; Whiteman etal., 2008 AtKUP6 √Osakabe etal., 2013 AtKUP7 √ √ Han etal., 2016 AtKUP8 √Jaquinod etal., 2007; Whiteman etal., 2008 AtKUP12 √ √ Kleffmann etal., 2004; Jaquinod etal., 2007; Whiteman etal., 2008 HvHAK1 √Senn etal., 2001 OsHAK1 √Chen etal., 2015 OsHAK5 √Yang etal., 2014 OsHAK10 √Bañuelos etal., 2002 OsHAK21 √Shen etal., 2015 PpHAK2 √Haro etal., 2013 PpHAK3 √Haro etal., 2013 Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 6 March 2019 | Volume 10 | Article 281 Xu et al., 2006). AKT1 possesses an intrinsic K+ sensor reducing channel conductance at submillimolar external K+ concentrations. Despite this K+ sensor, upon activation by the CIPK/CBL complex at low external K+, the homomeric AKT1 channels open at voltages positive of EK, a condition potentially resulting in cellular K+ leakage (Geiger et al., 2009). Incorporation of the AtKC1 subunit into the channel complex, however, shifts the voltage dependence of AKT1 toward more negative potentials (ca. −70mV) to prevent K+ loss (Geiger et al., 2009; Wang et al., 2010; Wang etal., 2016). In other words, AKT1/KC1 heteromerization renders the channel more efficient at blocking K+ permeation in the outward direction. The physical interaction of the CIPK23/CBL1 complex is specific for AKT1 channels and does not involve the AtKC1 subunit. The gain-of-function mutation AtKC1-D (G322D substitution in transmembrane S6) was recovered in the cipk23 mutant background. AtKC1-D enhanced the inhibition of AKT1 channel activity and restricted K+ leakage through AKT1 under low-K+ conditions, thereby increasing the tolerance to nutrient stress (Wang et al., 2016). Although the double mutant akt1 KC1-D was sensitive to low-K+, indicating that KC1-D action is through AKT1, an additional indirect effect of mutation KC1-D through HAK5 cannot be ruled out. By inhibiting AKT1 and shifting its voltage dependence toward a more negative direction, the plasma membrane could become hyperpolarized in the KC1-D mutant, thereby enhancing the expression and activity of HAK5 and improving net K+ uptake. Several mechanisms for AKT1 deactivation have been proposed. The PP2C-type protein phosphatase AIP1 interacts with and inactivates the AKT1 channel, counteracting the activation by CIPK23in oocytes (Lee etal., 2007). In principle, these findings are evidence of a phosphorylation/dephosphorylation switch that regulates AKT1 channel activity, but it should be noted that no phosphorylation of AKT1 by CIPK23 and dephosphorylation by AIP1 has been demonstrated conclusively (Hashimoto etal., 2012). Instead, four components, CIPKs, CBLs, PP2Cs, and AKT1, appear to interact mutually and form a molecular complex whose specific composition could ultimately regulate channel activity (Lan et al., 2011). In this model, PP2C phosphatases interact with the kinase domain of CIPKs to counteract kinasemediated activation of AKT1. Upon calcium signaling, CBLs interact with PPC2C to inhibit their phosphatase activity while simultaneously activating the partnering CIPKs. On the other hand, CBL10, a regulatory subunit of CIPK24/SOS2 but not of CIPK23, also interacts directly with AKT1 and negatively modulates AKT1 activity by competing with CIPK23 to bind AKT1 (Ren et al., 2013). Since CBL10 function is related to salinity stress rather than to mineral nutrition (Kim et al., 2007; Quan et al., 2007; Lin et al., 2009), this cross-regulation may constitute a mechanism to prevent salinity-induced K+ loss though AKT1. In line with this, the nitric oxide (NO) that accumulates under salinity stress also inhibits the K+ uptake mediated by AKT1. The link is indirect since NO triggered the accumulation of pyridoxal 5′-phosphate (PLP), an active form of vitamin B6, that in turn repressed the activity of AKT1in Xenopus oocytes and Arabidopsis root protoplasts (Xia et al., 2014). In Arabidopsis, the voltage-gated channel GORK (guard cell outward-rectifying K+) is the major outward-rectifying K+ channel in guard cells where it contributes to K+ efflux for decreasing turgor and stomatal closure (Ache etal., 2000; Hosy et al., 2003). In addition, GORK is expressed in root outer cell layers (epidermal, root hairs, and cortex) of Arabidopsis and thus GORK is considered a major pathway for stressinduced K+ leakage from root cells, e.g. by exposure of roots to high salt (Ivashikina et al., 2001; Demidchik et al., 2010; Demidchik etal., 2014). Production of hydroxyl radicals (HO˙) in salinized roots stimulates a dramatic K+ efflux mediated by GORK from root cells (Demidchik et al., 2010). The oxidative and salt stresses cause programmed cell death (PCD) and collapse membrane potential in root cells of Arabidopsis thaliana in a K+-dependent manner. Accordingly, the Arabidopsis gork1-1 mutant showed no K+ outwardly directed currents in response to HO˙. Besides, after exposure to high NaCl levels, the mutant gork1-1 displayed lower activity of proteases and endonucleases for PCD, which in the wild type was dramatically enhanced by K+ loss in root cells (Demidchik et al., 2010). Both the expression level and channel activity of GORK are significantly upregulated by increasing levels of the abscisic acid (ABA) and jasmonate. Stimuli that elevated endogenous ABA concentrations, e.g. drought, osmotic stress, or cold, led to the up-regulation of GORK transcripts (Becker etal., 2003; Suhita, 2004) while treatment with salicylic acid inhibited the presence of active GORK channels and improved salinity tolerance through prevention of K+ efflux. Recent studies demonstrated that calcium-dependent protein kinase 21 (CPK21) phosphorylated GORK and suggested that 14-3-3 proteins control GORK activity through binding with CPK21. This kinase phosphorylates three amino acid residues in the C-terminus of GORK, T344, S518, and S649. Binding of 14-3-3 to CPK21 strongly stimulated its kinase activity and increased TABLE 2 | Comparison of AKT1 channels and HAK1/HAK5 transporters from Arabidopsis and rice working at different ranges of external K+ concentrations. The uptake systems working in addition to AKT1 and HAK1/HAK5 likely include CHX exchangers (Zhao etal., 2008) and cyclic nucleotide-gated channels (CNGC) that may contribute to K+ absorption when the external K+ concentration is sufficiently high (Caballero etal., 2012). External [K+] Arabidopsis Rice <10μM AtHAK5 OsHAK1 10–100μM AtHAK5 AtKUP7 AtAKT1 OsHAK1 OsHAK5 OsAKT1 100–200μM AtHAK5 AtAKT1 OsHAK1 OsHAK5 OsAKT1 200μM–1mM AtAKT1 OsHAK1 OsHAK5 OsAKT1 1–10mM AtAKT1 Other systems (CHX, CNGC) OsAKT1 Unknown systems >10mM Other systems (CHX, CNGC) Unknown systems Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 7 March 2019 | Volume 10 | Article 281 GORK phosphorylation (van Kleeff et al., 2018). On the other hand, the phosphatase AtPP2CA interacts physically with GORK inhibiting its current (Lefoulon et al., 2016). Thus, AtPP2CA could have an antagonist role to CPK21 on the regulation of GORK (van Kleeff et al., 2018). These results imply that the salinity-induced membrane depolarization together with the Ca2+- and CPK21-dependent phosphorylation act together to activate GORK and to repolarize the plasma membrane by means of releasing part of the cytosolic K+. Moreover, the peak of the salt-induced K+-efflux in the aha2 mutant, devoid of a major isoform of the plasma membrane H+-ATPase, was stronger and more sustained than in the wild-type, suggesting that H+-pumps take over membrane repolarization after the initial K+-loss to re-enact K+ uptake (van Kleeff et al., 2018). Recently, Saponaro et al. (2017) showed that 14-3-3 proteins are also capable of modulating KAT1, although in this case 14-3-3 bound directly to the KAT1 C-terminus affecting both the voltage dependency of the channel and the number of channel molecules in the membrane (Sottocornola etal., 2008). K+-H+ symport has long been considered the likely catalytic mechanism of plant KT/HAK/KUP transporters based on the demonstration that K+-H+ symport operates in K+-starved Neurospora crassa and on thermodynamical considerations regarding the steep K+ gradient that KT/HAK/KUP proteins are able to achieve across cell membranes that exceeds what could bereached by coupling the K+ uptake to the membrane potential solely (Rodriguez-Navarro, 2000). Until recently, efforts to express plant KT/HAK/KUP proteins in Xenopus oocytes to measure K+ currents had failed, but work with the DmHAK5 transporter from Venus flytraps showed that co-expression of the corresponding cRNA with that of CBL9/CIPK23 (but not DmHAK5 alone) generated inward K+ and Rb+ currents in Xenopus oocytes that were stimulated by low external pH (Scherzer etal., 2015). Moreover, salt bladders of the halophyte Chenopodium quinoa that accumulate salts to very high concentrations express a HAK-like activity driving high-affinity and selective K+ uptake that was dependent on acidic external pH and by the CIPK23/CBL1 kinase module of Arabidopsis (Bohm etal., 2018). Electrophysiological recordings in rice roots showed that the activity of OsHAK1 was strongly electrogenic and depolarizing. Plots of the OsHAK1-dependent K+-induced membrane depolarization had a slope of 29 mV per decade of external K+ concentration, suggesting the co-transport of two monovalent cations (a 59 mV slope is to be expected from an uniprot transport moving only single K+ ions) (Nieves-Cordones etal., 2017). Together, these data strongly suggest that plant KT/ HAK/KUP proteins operate as K+-H+ symporters. Residues involved in K+ binding and/or transport have not been identified; however, mutant proteins with residue substitutions of members of the KT/HAK/KUP family have been described as showing modified affinity for K+, Na+, and/or Cs+, or increased Vmax (Aleman et al., 2014). HAK1-like transporters are subject to complex transcriptional and post-translational regulations, although studies have been carried out almost exclusively in Arabidopsis AtHAK5 (Jung et al., 2009; Rubio et al., 2014; Ragel et al., 2015). Under any stress conditions that directly affect K+ acquisition, such as K+ deprivation or salinity, high-affinity K+ uptake systems should be transcriptionally or post-translationally activated in order to maintain the K+ supply and K+/Na+ homeostasis. Accordingly, all characterized HAK1-like transporters exhibit low expression levels in roots under control conditions, are highly up-regulated upon K+ deprivation and rapidly down-regulated when K+ is resupplied (reviewed by (Li et al., 2018)). Furthermore, it has been commonly observed that other ions, particularly NH4+, NO3−, Na+, and Pi, also regulate the expression of HAK1-like genes and not always in the same way (Nieves-Cordones et al., 2019). For example, NH4+ reduces the transcriptional induction by K+ starvation of the pepper CaHAK1 (Martinez-Cordero et al., 2005) and Arabidopsis AtHAK5 (Qi et al., 2008), but enhances the expression of LeHAK5 in tomato (Nieves-Cordones et al., 2007). The presence of NaCl prevents the induction of LeHAK5 by K+ starvation (Nieves-Cordones et al., 2007), but provokes a strong and transient up-regulation of HvHAK1 (Fulgenzi et al., 2008). Thus, the Arabidopsis model cannot be completely extended to other plant species, crops among them. In contrast to HAK1-like transporters, KT/HAK/KUP proteins belonging to clusters II–V show diverse expression patterns and most of them do not exhibit transcriptional regulation in response to K+ deficiency (Ahn et al., 2004; Li et al., 2018). For example, AtKUP7 (cluster V, plasma membrane) transcript is not induced by low-K+ (Han etal., 2016) and AtKUP12 (cluster III, chloroplast) is down-regulated after K+ resupply (Armengaud et al., 2004). Regarding the transcriptional regulation of genes encoding HAK1-like transporters, it has been shown that the effect of the nutrient deficiency and salt stresses on transcriptional expression of AtHAK5 and LeHAK5 is associated with changes in the root cell membrane potentials (Nieves-Cordones et al., 2008; Rubio et al., 2014); the hyperpolarization of the plasma membrane of root cells induces transcription of both genes. Supporting this, ThHAK5 of Thellungiella halophila (salt cress, a.k.a. Eutrema salsuginea) is expressed to higher levels than AtHAK5 under salt stress, while roots of T. halophila maintained a more negative membrane potential than Arabidopsis roots (Volkov and Amtmann, 2006; Alemán et al., 2009b; Rubio etal., 2014). Besides membrane hyperpolarization, the expression of AtHAK5 is also induced, under K+-limiting conditions, as result of signaling cascades that involve ROS production, phytohormones, and transcription factors. Low-K+ stress, alike other nutrient-deprived conditions, promotes an increase of ethylene that positively regulates ROS production in roots (Shin and Schachtman, 2004; Jung et al., 2009). Roots deprived of K+ induce the expression of genes involved in ethylene biosynthesis and signaling, and in ROS metabolism, promoting two-fold higher levels of ethylene and the increase in hydrogen peroxide (H2O2) concentrations. Both ethylene and ROS give rise to enhanced transcription of HAK5 in Arabidopsis and tomato (Rodenas et al., 2018). In Arabidopsis, H2O2 produced by the NADPH oxidase RHD2/RbohC regulates the expression of AtHAK5 in response to K+ deficiency (Shin and Schachtman, 2004) and it has been proposed that peroxidase RCI3 (Rare Cold Inducible gene 3) contributes to ROS production during Arabidopsis root response to K+ deficiency (Kim et al., 2010). In the case of ethylene-induced AtHAK5 transcription, the intermediaries in ethylene signaling CTR1 (Constitutive Triple Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 8 March 2019 | Volume 10 | Article 281 Response (1) and EIN2 (Ethylene Insensitive (2) are partially involved. Results also suggest the existence of other signaling pathways or an EIN2-independent ethylene route that may play an important role in low-K+ signaling (Jung etal., 2009). Genetic hierarchy indicates that ethylene signaling acts upstream of ROS when plants are deprived of K+ (Jung et al., 2009). Nevertheless, it has also been speculated that a positive feedback may stimulate ethylene-induced ROS production (Wang etal., 2002). Other hormones have been shown to be involved in K+ deprivation signaling and response, for instance jasmonic acid (Armengaud et al., 2004), auxin (Jung et al., 2009; Hong et al., 2013), ABA (Kim et al., 2010), cytokinins (Nam et al., 2012), and gibberellins through DELLA proteins (Oliferuk etal., 2017). Cytokinins are known to regulate macronutrient homeostasis by controlling the expression of nitrate, phosphate, and sulfate transporters. Cytokinin content decreases under K+-starved conditions, and cytokinin-deficient mutants, under same conditions, display enhanced accumulation of both ROS and AtHAK5 transcripts (Nam et al., 2012). By contrast, cytokinin-receptor mutants lost the responsiveness to low-K+, including ROS accumulation and root hair growth. Interestingly, the cytokinin/ethylene ratio is positively correlated with tomato shoot biomass, suggesting that the balance between both hormones is important in determining the plant vigor at low-K+ supply, but with an inverse role in tomato compared to Arabidopsis, where cytokinin/ethylene ratio was negatively correlated with tolerance to K+ deprivation (Jung et al., 2009; Nam et al., 2012). In addition to low nutrient conditions, salt stress (and presumably other abiotic stresses) results in modifications of AtHAK5 expression or the low-K+ response. Mild salt stress does not induce AtHAK5 expression but its expression levels gradually increased following an increase in NaCl concentrations (Ahn et al., 2004; Hong etal., 2013). This suggests that plants may recognize high Na+ levels as K+ deprivation. However, the induction of AtHAK5 expression by low K+ was suppressed by salt stress in Arabidopsis (Nieves-Cordones et al., 2010), but not in T. halophila (Alemán et al., 2009a). As discussed above, under salt stress conditions, T. halophila registers a more negative root membrane potential than A. thaliana (Volkov and Amtmann, 2006), which may explain the expression of ThHAK5 under these conditions (Alemán et al., 2009a). In recent years, several transcription factors (TFs), and their target sequences, have been identified in the AtHAK5 promoter. Among them, ARF2 (Auxin Response Factor 2) is the only one described so far to work as negative regulator of AtHAK5 transcription (Zhao et al., 2016). Interestingly, ARF2 has been found to beinvolved in many phytohormone-signaling pathways, but it seems not to participate in auxin signaling. Under K+- sufficient conditions, channel-mediated K+ uptake would beenergetically more favorable than symport through AtHAK5, and hence AtHAK5 should be shut down (Zhao et al., 2016). In those conditions, ARF2 binds to the auxin-responsive elements (AuxREs) within the AtHAK5 promoter and represses transcription. When plants are subjected to low-K+ stress, ARF2 is rapidly phosphorylated by an unknown kinase and loses DNA binding activity. ARF2 is removed from the AtHAK5 promoter, which relieves the repression on AtHAK5 transcription. In turn, other TFs bind to the AtHAK5 promoter and activate its transcription. These TFs up-regulating AtHAK5 expression under K+ starvation include RAP2.11, which binds to the ethylene-responsive element (ERE) and the GCC-box of the AtHAK5 promoter, and whose expression is stimulated by ethylene and ROS, alike AtHAK5 (Kim etal., 2012). TFs DDF2, JLO, bHLH121, and TFII_A also interact with the upstream region of AtHAK5, but the specific binding motif for each of them has not been identified yet (Hong et al., 2013). All of these transcription factors are sufficient to activate AtHAK5 expression in heterologous systems, but none of them is absolutely required. When K+ is resupplied, ARF2 becomes dephosphorylated again and represses AtHAK5 expression (Zhao et al., 2016). Thus, it is apparent that regulation of the activity of TFs acting on AtHAK5 transcription (positively or negatively) is necessary to determine cooperatively the accumulation of the corresponding transcripts (Santa-Maria et al., 2018). Although a general nutrient deprivation stimulus is sufficient for the transcriptional activation of AtHAK5 and LeHAK5 genes, a reduction of internal K+ is required for the induction of a functional HAK5-mediated high-affinity K+ uptake in Arabidopsis and tomato roots (Rubio et al., 2014), suggesting the existence of post-transcriptional regulation in planta. Recently, it was shown that activation of high-affinity K+ uptake mediated by AtHAK5 (Ragel et al., 2015), DmHAK5 from Venus flytraps (Scherzer et al., 2015), and CqHAK from quinoa (Bohm et al., 2018) is mediated by the CBL-interacting protein kinase (CIPK)/ calcineurin B-like protein (CBL) complex comprising CIPK23 and CBL1/9 proteins of Arabidopsis. Notably, this CIPK23/CBL1,9 module also activates AKT1 channel, that together with AtHAK5 constitutes the main K+ uptake pathway in Arabidopsis roots (Xu et al., 2006; Lee et al., 2007). Both the protein kinase AtCIPK23 and the Ca2+ sensor AtCBL1 are necessary and sufficient for activation of the high-affinity K+ transporter AtHAK5 in yeast (Ragel et al., 2015). Besides AtCBL1, other CBLs (AtCBL8/9/10) are able to bind AtCIPK23 and activate AtHAK5 to complement K-uptake defective yeast growth. The reduction in the K+ concentration produces a specific Ca2+ signature in the cytosol (Figure 3) (Behera et al., 2017) that would berecorded by AtCBL1, promoting CIPK23/CBL1 complex formation, and the activation of AtHAK5 by phosphorylation at the cytosolic N-terminus (Ragel et al., 2015), in a similar way that was described for AKT1 (Xu et al., 2006; Lee et al., 2007). The enhancement of growth at low-K+ of yeast cells co-expressing AtHAK5, AtCIPK23, and AtCBL1 seems to result from modification of the kinetic properties of the transporter (Km decrease and Vmax increase), likely through the phosphorylation-induced conformational changes of AtHAK5 (Ragel etal., 2015). However, since physical interaction between CIPK23/CBL1 and AtHAK5 is also required for full activation of AtHAK5in yeast, the trafficking of the transporter to plasma membrane has been proposed as a second mechanism of AtHAK5 regulation by CIPK23/CBL1 complex. Supporting this idea, the AtHAK5 protein was mainly detected in the endoplasmic reticulum of K+-sufficient plants, while K+ starvation produced an enrichment of AtHAK5 protein in the plasma membrane (Qi et al., 2008). Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 9 March 2019 | Volume 10 | Article 281 In heterologous systems, the Arabidopsis CIPK23/CBL1,9 complex enabled the activation of various members from clade Iof KT/ HAK/KUP transporters, such as pepper CaHAK1 (Ragel et al., 2015) and Venus flytrap DmHAK5 (Scherzer et al., 2015), but not of tomato SlHAK5 or the Eutrema salsuginea EsHAK5 (Ragel etal., 2015). These results suggested that the activation mechanism by CIPK23/CBLs complexes is evolutionarily conserved, but not the phosphorylation site and/or the target sequence recognition, which may vary among distant plant species. Accordingly, a quimeric tomato HAK5 protein that contained the 15 first amino acids of CaHAK1 could be activated by CIPK23/CBL1 in yeast (Ragel et al., 2015). Since the two main contributors to K+ uptake in Arabidopsis, AKT1 and HAK5, are regulated by the CIPK23/CBL1,9 complex, the coordinated regulation of these transport systems deserves attention. Under K+-sufficient conditions, K+ uptake by HAK5 would beenergetically more expensive than permeation through the AKT1 channel. The H+-pumping activity of plasma membrane ATPases, which is used for many secondary transport processes, creates per se an electrical charge (negative inside) that suffices to draw significant amounts of K+ into the cytosol. At a regular steady membrane potential of −120 to −180mV, root epidermal cells could sustain a 100–1,000-fold inward-directed gradient of K+. However, coupling K+ uptake to H+ influx not only returns H+ to the cytoplasm but also is more depolarizing than simple K+ permeation, which in turn imposes a greater demand on the H+-pumps and ATP consumption. We speculate that under such conditions of K+ sufficiency, the plasma membrane is not hyperpolarized (or not enough), signaling phytohormones are not produced, and therefore transcription of HAK5 is not activated. AKT1 would be operational through the physical interaction with CIPK23 (and possibly other CIPKs) (Lee et al., 2007). As the K+ concentration outside decreases, the function of AKT1 becomes increasingly hampered and full activation by the Ca2+- dependent CIPK23/CBL1,9 complex is required to sustain K+ uptake, while the KC1 safeguard prevents K+ leakage through AKT1 (Wang etal., 2016). CIPK23 is known to display different states of activation, depending on factors that affect the activation of CIPKs by upstream kinases (Barajas-Lopez et al., 2018) and CBL binding (Chaves-Sanjuan et al., 2014). Thus, a mild K+ deprivation may produce a partially activated CIPK23 that would becompetent for activating AKT1 but not HAK5, whereas severe K+ deprivation leads to HAK5 transcription and to full activation of CIPK23, which would then becompetent for activating HAK5 (Ragel etal., 2015). The CIPK23 is itself induced transcriptionally by low-K+ stress (Xu et al., 2006), which could also enhance the response to nutritional stress. The participation of Ca2+ sensors in high-affinity K+ uptake could mechanistically connect K+ starvation with other abiotic stresses, for instance: salinity, water availability, oxygen deficiency (hypoxia) or absence (anoxia), mechanical stress, cold stress, heavy metal stress, and other nutrient deprivations, all sharing cytosolic free Ca2+ as a second messenger (Wilkins et al., 2016). Current thinking is that the specificity of Ca2+ signaling is determined by the amplitude and duration (and possible oscillation) of the cytosolic Ca2+ increase, often referred to as the “calcium signature” that is elicited by the stimulus. K+ deficiency evokes two successive Ca2+ signals in roots exhibiting different spatial and temporal specificity (Behera et al., 2017). The first one is characterized by a transient and fast Ca2+ increase within 1 min in the postmeristematic elongation zone (most prominently in the vascular tissue and endodermis), followed by a Ca2+ return nearly to basal concentrations in <7 min. The second wave (secondary Ca2+ FIGURE 3 | Regulatory circuitry regulating AtHAK5 expression and activity. K+ starvation is probably sensed as hyperpolarization of the plasma membrane, which, together with elevated ethylene and ROS levels, leads to expression of the HAK5 gene. Several transcriptional activator and repressor factors have been identified, but their placement in specific signaling pathways is uncertain. Subsequently, calmodulin-like (CML) and calcineurin B-like (CBL) Ca2+-binding proteins recruit and activate protein kinases ILK1 and CIPK23 that facilitate the trafficking of HAK5 to the plasma membrane and its biochemical activation, respectively. CIPK23 also stimulates the K+-uptake channel AKT1. K+ replenishment depolarizes the membrane and returns the system to homeostatic levels. Ragel et al. Regulation of K+ Nutrition in Plants Frontiers in Plant Science | www.frontiersin.org 16 March 2019 | Volume 10 | Article 281 of central importance for plant nutrition and deserve additional research. The availability of novel genetically encoded K+ sensors (Bischof etal., 2017) that could betargeted to various cellular compartments of predefined cells and tissues will be powerful tools to monitor the dynamics of cellular K+ with unprecedented spatiotemporal resolution. AUTHOR CONTRIBUTIONS All authors have contributed to literature search, discussion, and writing of the manuscript. PR and JP assembled all sections. PR and FQ prepared the Figures. All authors checked and approved the manuscript. FUNDING This work was supported by grant BIO2015-70946-R to FQ, and by grants BFU2015-64671-R and BIO2016-81957-REDT from AEI-MINECO (co-financed by the European Regional Development Fund), and the SSAC grant PJ01318205 from the Rural Development Administration, Republic of Korea, to JP. ACKNOWLEDGMENTS We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI). REFERENCES Ache, P., Becker, D., Ivashikina, N., Dietrich, P., Roelfsema, M. R. G., and Hedrich, R. (2000). GORK, a delayed outward rectifier expressed in guard cells of Arabidopsis thaliana, is a K+-selective, K+-sensing ion channel. FEBS Lett. 486, 93–98. doi: 10.1016/S0014-5793(00)02248-1 Ahmad, I., and Maathuis, F. J. (2014). Cellular and tissue distribution of potassium: physiological relevance, mechanisms and regulation. J. Plant Physiol. 171, 708–714. doi: 10.1016/j.jplph.2013.10.016 Ahn, S. 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