Potassium Channels

Kidney International (1995) 48, 1010–1016; doi:10.1038/ki.1995.383

An ATP-regulated, inwardly rectifying potassium channel from rat kidney (ROMK)

Steven C Hebert

Laboratory of Molecular Physiology and Biophysics, Renal Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Steven C Hebert MD, Brigham and Women's Hospital, Department of Medicine, Renal Division, 75 Francis Street, Boston, Massachusetts 02115, USA.

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Abstract

Potassium channels exhibit a wide functional diversity making them well suited for their broad roles in renal (and other) cells [1, 2]. Potassium channels can be classified into two broad groups based on their functional/biophysical properties: the delayed or outward rectifiers that are activated by depolarizing potentials and the inward rectifiers that include the classical (strongly) inwardly rectifying K+ channel and the more weakly inwardly rectifying ATP-sensitive potassium (KATP) channels [1, 3–7]. The inward rectifiers are characterized by a lack of significant gating by voltage and by their ability to conduct potassium more readily in the inward than outward direction. The classical (strong) and KATP-type of inward rectifiers have been identified in a variety of excitable and nonexcitable cells. The strong inward rectifiers appear to function in maintaining the resting membrane potential and in regulating excitability (such as in cardiac muscle cells). ATP-sensitive potassium channels, on the other hand, open and close in response to cellular metabolic events and may serve important roles in some cells during ischemia. Renal KATP channels, while sharing many of the properties and characteristics of KATP channels found in other tissues (such as pancreatic beta-cell and cardiac muscle cells [3]), lack sensitivity to TEA, have a much lower sensitivity to sulfonylureas (such as glyburide, a high affinity inhibitor of KATP channels found in heart and beta-cells), and require higher (that is, mM) concentrations of ATP to inhibit channel activity [1, 7].

In the kidney, the apical (K+ secretory) KATP channel serves a number of important roles in renal electrolyte transport [1]. In the thick ascending limb of Henle (TAL; both medullary, MTAL, and cortical, CTAL, segments; Fig. 1), KATP channels are the dominant conductance in apical plasma membranes and provide a crucial K+ efflux pathway for potassium entering cells via the apical Na+:K+:2Cl- cotransporter [1]. This recycling of potassium ensures that an adequate supply of luminal potassium is provided for efficient function of the Na+:K+:2Cl- cotransporter [1]. In addition, this channel mediates the apical component of a transcellular (basolateral-to-apical) current flow that returns to the basolateral side via the paracellular pathway predominantly as a sodium current [8]. This provides for one-half of the net transepithelial movement of sodium [9]. Two types of inwardly rectifying and ATP-sensitive K+ channels have been identified on apical membranes of TAL segments by patch clamp [10, 11]. Wang and coworkers [10] found a 20 to 30 pS K+ channel in rabbit TAL that had a high open probability (Po), was inhibited by ATP (mM) and not sensitive to TEA (referred to as the "low conductance" channel). On the other hand, a different KATP channel was identified on apical membranes of rat TAL by Greger and coworkers [11–13]; this channel also had a high Po and was ATP-sensitive but had a higher unitary conductance of approx70 pS, was highly sensitive to reductions in cytosolic side pH (50% reduction in Po by a 0.2 pH unit decrease), and exhibited sensitivity to quinine or quinidine, TEA and Ca2+ (referred to as the "intermediate conductance" channel). Recently, Wang found both the low (approx30 pS) and intermediate (approx72 pS) conductance KATP channels in the same patches of rat TAL apical membranes [14]. He also confirmed that the intermediate conductance KATP channel is sensitive to quinidine and acidic pH while the low conductance channel is insensitive to quinidine. In addition, the low, but not the intermediate, conductance channel is inhibited by high (approx250 microM) gliburide. These studies demonstrate that there are two distinct channel types in apical membranes of TAL and that these channels can be distinguished by single channel conductances and their sensitivities to channel inhibitors.

A functionally similar, if not identical, low conductance, inwardly rectifying KATP channel has been identified in apical membranes of principal cells in the cortical collecting duct (CCD) where it mediates K+ secretion into urine (Fig. 1) [1, 7, 15, 16]. The KATP channel in rat principal cells is dually regulated by ATP: high MgATP concentrations reversibly block channel activity (K1/2 = 0.6 to 1.0 mM) while lower concentrations of MgATP are required to maintain channel activity [1, 7, 17, 18]. The mechanism for ATP-mediated block of the principal cell KATP channel is unclear at present but may represent direct binding of nucleotide to the channel itself with a resulting change in channel conformation to the closed state and/or to altering the activity of the channel by regulating the phosphorylation of the channel itself, or some other protein involved to modulating channel activity. The stimulatory effect of low ATP concentration, however, clearly relates to regulation of channel activity by phosphorylation-dephosphorylation processes [18]: (i) channel activity rapidly diminishes (run-down) on patch excision unless the cytosolic face is exposed to low concentrations of MgATP; (ii) generally the 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-hydrolyzable ATP analogues cannot maintain or restore channel activity; (iv) in patches in which channel activity is maintained by MgATP alone, the PKA inhibitor (PKI) reversibly reduces channel activity, providing evidence for an important role for endogenous PKA; and (v) PKC reversibly inhibits channel activity and antagonizes the stimulatory effect of PKA, a process that is Ca2+-dependent [19]. In further studies Wang and Giebisch [17, 18] demonstrated that the ratio of ATP to ADP and cell pH are also important regulators of the small conductance KATP channel in the apical membranes of principal cells. KATP channel activity in rat principal cells is also inhibited by activation of protein kinase C [19] or calcium-calmodulin-dependent kinase II [20] or by arachidonic acid [21].

Much less is known about the regulation of the apical KATP channels in the TAL than in the CCD; however, we previously suggested that AVP (presumably cyclic AMP-dependent activation of PKA and subsequent phosphorylation of the channel or an associated regulatory protein) activated the K+ conductance of the apical membrane in mouse MTAL [22, 23]. Reeves and coworkers have provided more direct evidence for this [24]. They showed that Ba2+-sensitive, voltage-dependent 86Rb+ influx in membrane vesicles from rabbit outer medulla was activated by cAMP-dependent protein kinase. Wang [14] has confirmed this effect of cAMP-PKA by showing activation of the low conductance KATP channel in cell attached patches by AVP or cAMP and in excised patches by the catalytic subunit of PKA.

Finally, it should be noted that large conductance (maxi-K+), Ca2+-activated K+ channels have been identified in apical membranes of both TAL [25, 26] and CCD [1, 27–29]. These voltage-gated channels are normally quiescent but can be activated by microM cytosolic Ca2+, are inhibited by TEA (more sensitive to TEA than the intermediate conductance KATP channel), and are insensitive to ATP. Since K+(Rb+) secretion and the transepithelial voltage in the CCD are not blocked by luminal TEA [16, 28], it is generally thought that this apical maxi-K+ channel is not directly involved in K+ secretion by this nephron segment. The maxi-K+ channel may function, however, as a K+ efflux pathway during cell swelling [1, 7, 30].

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