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An ATP-Regulated, Inwardly Rectifying Potassium Channel from Rat Kidney (ROMK)

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An ATP-Regulated, Inwardly Rectifying Potassium Channel from Rat Kidney (ROMK) View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Kidney International, Vol. 48 (1995), pp. 1010—1016 An ATP-regulated, inwardly rectifying potassium channel from rat kidney (ROMK) STEVEN C.HEBERT Laboratoiy of Molecular Physiology and Biophysics, Renal Division, Department of Medicine, Brigham and Women c Hospital, and Harvard Medical School, Boston, Massachusetts, USA Potassium channels exhibit a wide functional diversity makingWang and coworkers [101 found a 20 to 30 pS K channel in them well suited for their broad roles in renal (and other) cells [1,rabbit TAL that had a high open probability (Po), was inhibited by 21.Potassiumchannels can be classified into two broad groupsATP (mM) and not sensitive to TEA (referred to as the "low based on their functional/biophysical properties: the delayed orconductance" channel). On the other hand, a different KATP outward rectifiers that are activated by depolarizing potentials andchannel was identified on apical membranes of rat TAL by Greger the inward rectifiers that include the classical (strongly) inwardlyand coworkers [11—13]; this channel also had a high Po and was rectifying K channel and the more weakly inwardly rectifyingATP-sensitive but had a higher unitary conductance of —70 pS, ATP-sensitive potassium (KATP) channels [1, 3—7]. The inwardwas highly sensitive to reductions in cytosolic side pH (50% rectifiers are characterized by a lack of significant gating byreduction in Po by a 0.2 pH unit decrease), and exhibited voltage and by their ability to conduct potassium more readily insensitivity to quinine or quinidine, TEA and Ca2 (referred to as the inward than outward direction. The classical (strong) andthe "intermediate conductance" channel). Recently, Wang found K.fl-type of inward rectifiers have been identified in a variety ofboth the low (—30 pS) and intermediate (—72 pS) conductance excitable and nonexcitable cells. The strong inward rectifiersKATP channels in the same patches of rat TAL apical membranes appear to function in maintaining the resting membrane potential[14]. He also confirmed that the intermediate conductance KATP and in regulating excitability (such as in cardiac muscle cells).channelis sensitive to quinidine and acidic pH while the low ATP-sensitive potassium channels, on the other hand, open andconductance channel is insensitive to quinidine. In addition, the close in response to cellular metabolic events and may servelow, but not the intermediate, conductance channel is inhibited by important roles in some cells during ischemia. Renal KArphigh (—250 LM) gliburide. These studies demonstrate that there channels, while sharing many of the properties and characteristicsare two distinct channel types in apical membranes of TAL and of KATP channels found in other tissues (such as pancreatic f3-cell that these channels can be distinguished by single channel con- and cardiac muscle cells [31),lacksensitivity to TEA, have a muchductances and their sensitivities to channel inhibitors. lower sensitivity to sulfonylureas (such as glyburide, a high affinity A functionally similar, if not identical, low conductance, in- inhibitor of KATP channels found in heart and 13-cells), andwardly rectifying KATP channel has been identified in apical require higher (that is, mM) concentrations of ATP to inhibitmembranes of principal cells in the cortical collecting duct (CCD) channel activity [1, 7]. where it mediates K secretion into urine (Fig. 1) [1, 7, 15, 16]. In the kidney, the apical (K secretory) KA1.P channel serves a The KATP channel in rat principal cells is dually regulated by ATP: number of important roles in renal electrolyte transport [1]. In the thick ascending limb of Henle (TAL; both medullary, MTAL, andhigh MgATP concentrations reversibly block channel activity (K112 =0.6to 1.0 mM) while lower concentrations of MgATP are cortical, CTAL, segments; Fig. 1), KATP channels are the domi- nant conductance in apical plasma membranes and provide arequired to maintain channel activity [1, 7, 17, 181. The mecha- crucial K efflux pathway for potassium entering cells via thenism for ATP-mediated block of the principal cell KATP channel is unclear at present but may represent direct binding of nude- apical Na:K:2Cl cotransporter [ii. This recycling of potas-otide to the channel itself with a resulting change in channel sium ensures that an adequate supply of luminal potassium is conformation to the closed state and/or to altering the activity of provided for efficient function of the Na:K:2Cl cotransporter the channel by regulating the phosphorylation of the channel [1]. In addition, this channel mediates the apical component of a transcellular (basolateral-to-apical) current flow that returns toitself, or some other protein involved to modulating channel the basolateral side via the paracellular pathway predominantly asactivity. The stimulatory effect of low ATP concentration, how- a sodium current [8]. This provides for one-half of the netever, clearly relates to regulation of channel activity by phosphor- transepithelial movement of sodium [9]. Two types of inwardlyylation-dephosphorylation processes [18]: (i) channel activity rap- rectifying and ATP-sensitive K channels have been identified onidly diminishes (run-down) on patch excision unless the cytosolic face is exposed to low concentrations of MgATP; (ii) generally the apical membranes of TAL segments by patch clamp [10, 11]. catalytic subunit of cAMP-dependent protein kinase, PKA, is also required for channel maintenance and PKA, and together with MgATP can restore channel activity after run-down; (iii) non- © 1995 by the International Society of Nephrology hydrolyzable ATP analogues cannot maintain or restore channel 1010 Hebert: ROMK in the distal nephron 1011 r Na K z ,'2C1 - 2K S. Fig. 1. Model for potassium recycling across apical membranes of the thick ascending limb and for potassium secretion in principal cells from the cortical collecting duct in rat kidney. See text for discussion. activity; (iv) in patches in which channel activity is maintained by An inwardly rectifying, ATP-regulated K channel, ROMK, MgATP alone, the PKA inhibitor (PKI) reversibly reduces chan- from rat kidney: A member of a family of inwardly rectifying nel activity, providing evidence for an important role for endog- potassium (IRK) channels enous PKA; and (v) PKC reversibly inhibits channel activity and antagonizes the stimulatory effect of PKA, a process that is Cloning and molecular diversity Ca2-dependent [19]. In further studies Wang and Giebisch [17, 18] demonstrated that the ratio of ATP to ADP and cell pH are We recently cloned a cDNA, ROMKI [31], encoding a —45 kD also important regulators of the small conductance KATP channelchannel protein with a novel channel topology (Fig. 2). Subse- in the apical membranes of principal cells. KATP channel activityquently, other inwardly rectifying K channels have been isolated in rat principal cells is also inhibited by activation of protein[31—39] and form a new and rapidly expanding family of potassium kinase C [19] or calcium-calmodulin-dependent kinase II [201 orchannels (IRK family; Fig. 3). The ROMK1 channel protein has by arachidonic acid [21]. two potential membrane-spanning helices (Ml and M2; Fig. 2) Much less is known about the regulation of the apical KATPmaking it quite distinct from voltage-gated or ligand-gated ion channels in the TAL than in the CCD; however, we previouslychannels [40, 41], and this topology is a characteristic feature of suggested that AVP (presumably cyclic AMP-dependent activa-these IRK channels. ROMKI is expressed in kidney and several tion of PKA and subsequent phosphorylation of the channel or another tissues, for example, brain, spleen, lung and eye [31, 42]. associated regulatory protein) activated the K1 conductance of Recent studies have demonstrated that the ROMK gene con- the apical membrane in mouse MTAL [22, 23]. Reeves andtains introns within the coding region [43—45], an unusual feature coworkers have provided more direct evidence for this [24]. Theyfor a mammalian K channel. Alternative splicing of ROMK showed that Ba2tsensitive, voltage-dependent 86Rb influx inexons yields several different transcripts: ROMK2a, ROMK2b membrane vesicles from rabbit outer medulla was activated byand ROMK3 (Fig. 2). All of the proteins produced by these cAMP-dependent protein kinase. Wang [14] has confirmed thisalternatively spliced transcripts form functional K channels effect of cAMP-PKA by showing activation of the low conduc-when expressed in Xenopus oocytes [36, 461. The alternative tance KATP channel in cell attached patches by AVP or cAMP and splicing occurs at both the 5'-coding and 3'-non-coding regions. in excised patches by the catalytic subunit of PKA. We do not know whether the alternative splice variation and use Finally, it should be noted that large conductance (maxi-K),of different polyadenylation signals which lead to varying lengths Ca2-activated K channels have been identified in apical mem-of the 3'UTRs (untranslated regions) have functional or regula- branes of both TAL [25, 26] and CCD [1, 27—29]. These voltage-tory significance for the ROMK isoforms (mRNA half-life, effi- gated channels are normally quiescent but can be activated by IIMciency of translation, etc.). The longer ROMK2b transcript may cytosolic Ca2t are inhibited by TEA (more sensitive to TEA thanaccount for the —3 kb mRNA observed on Northern blot analysis the intermediate conductance
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