Molecular diversity and regulation of renal potassium channels

Abstract

K(+) channels are widely distributed in both plant and animal cells where they serve many distinct functions. K(+) channels set the membrane potential, generate electrical signals in excitable cells, and regulate cell volume and cell movement. In renal tubule epithelial cells, K(+) channels are not only involved in basic functions such as the generation of the cell-negative potential and the control of cell volume, but also play a uniquely important role in K(+) secretion. Moreover, K(+) channels participate in the regulation of vascular tone in the glomerular circulation, and they are involved in the mechanisms mediating tubuloglomerular feedback. Significant progress has been made in defining the properties of renal K(+) channels, including their location within tubule cells, their biophysical properties, regulation, and molecular structure. Such progress has been made possible by the application of single-channel analysis and the successful cloning of K(+) channels of renal origin.

FIG. 1

Potassium transport along a simplified nephron. K⁺ is filtered and extensively reabsorbed along the proximal convoluted tubule (PCT). Some K⁺ enters the proximal straight tubule (PST) and the thin, descending limb of Henle’s loop (DTL). But extensive K⁺ reabsorption along the ascending thin limb of Henle (ATL) and along both the medullary (MTAL) and cortical (CTAL) portions of the thick ascending limb sharply reduce the amount of K⁺ by the time fluid has reached the beginning of the distal convoluted tubule (DCT). Regulated K⁺ secretion takes place in the connecting tubule (CNT), DCT, initial collecting duct (ICD), and cortical collecting duct (CCD), and reabsorption may occur in the terminal nephron segments, the outer (OMCD) and inner (IMCD) medullary collecting duct. The reabsorptive and secretory components of K⁺ transport in the loop of Henle and the further distally located nephron segments are subject to regulation, but transport in the proximal tubule does not control urinary K⁺ excretion. The arrow size represents relative magnitudes of K⁺ secretion and reabsorption.

FIG. 2

A model of a single nephron showing the function of renal K⁺ channels in proximal tubules, thick ascending limb (TAL), and cortical and outer medullary collecting duct (CCD).

FIG. 3

A model of a single nephron demonstrating the expression of currently known K⁺ channel genes.

FIG. 4

Classification of K⁺ channels and schematic representation of their secondary structure. A: the α-subunit of the 6-TM class of K⁺ channels: six transmembrane segments (S1-S6) and one pore (P). S4 represents the voltage sensor of Kv channels. The active channel is a tetramer and can also contain accessory (β) subunits. K⁺ channels belonging to this class include Kv1.1–1.10, IKCa, HERG, and KvLQT. B: unlike the other members of the 6-TM class, hSlo appears to have seven transmembrane segments (S0-S6) and the amino terminus is predicted to be located extracellulary. The S4 segment is well conserved, and the cytoplasmic tail contains a calcium-binding domain. The active channel is a heterotetramer and contains accessory (β) subunits. C: the α-subunit of the 2-P class of K⁺ channels: 4 transmembrane segments (S1-S4) and 2 pores (P1, P2). These channels do not have an S4 segment. K⁺ channels belonging to this class include TWIK, TRAAK, TASK, and TREK. D: MinK and the MinK-related peptides (MiRPs) contain a single transmembrane segment and function as accessory subunits for a variety of 6-TM channels. E: the single transmembrane subunit MinK (KCNE1).

FIG. 5

A model of proximal tubule cell illustrating the location and regulation of K⁺ channels. The single-channel conductance of the K⁺ channels is indicated. The luminal Na⁺-dependent glucose and other amino acid transporters are indicated by Na/S. The basolateral Na⁺-K⁺-ATPase is also shown.

FIG. 6

A model of TAL cell showing K⁺ channels and their regulation. The single-channel conductance of the K⁺ channels is indicated. The luminal Na⁺-K⁺-Cl⁻ cotransporter and the basolateral Na⁺-K⁺-ATPase are shown. 20-HETE, 20-hydroxyeicosatetraenoic acid; PKC, protein kinase C; PKA, protein kinase A; PKG, cGMP-dependent protein kinase; PTK, protein tyrosine kinase; CO, carbon monoxide; AA, arachidonic acid.

FIG. 7

A model illustrating the K⁺ channels and their regulation in principal cells from the CCD. The luminal epithelial Na⁺ channel (ENaC) and the basolateral Na⁺-K⁺-ATPase are shown. PKC, protein kinase C; PKA, protein kinase A; PKG, cGMP-dependent protein kinase; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; CaMK II, calcium and calmodulin-dependent kinase II; CO, carbon monoxide; NO, nitric oxide; AA, arachidonic acid; PP2A, protein phosphatase 2A; ADH, antidiuretic hormone.

FIG. 8

A cell model showing the mechanisms regulating the activity of apical K⁺ channels in the kidney. Possible mechanisms for interaction between basolateral Na⁺-K⁺-ATPase and apical K⁺ channels are illustrated (cross talk).

FIG. 9

A scheme illustrating the mechanism by which a low-K⁺ diet decreases the surface expression of ROMK channels in principal cells from the CCD. With adaptation to a low K⁺ intake, protein tyrosine kinase (PTK) activity increases. The augmented PTK increases the rate of endocytosis, thereby reducing the number of K⁺ channels in the apical membrane.

FIG. 10

Cell models showing the signaling pathways involved in modulation of apical K⁺ channels in principal cells by low K⁺ intake. See text for discussion.

FIG. 11

A cell model showing the signaling pathways involved in modulation of basolateral K⁺ channels in principal cells.

FIG. 12

Structure of the bacterial inward rectifier K⁺ channel KirBac1.1, illustrating the five structural regions of the pore. Mammalian inwardly rectifying K⁺ channels like ROMK are believed to be structurally similar.

FIG. 13

A schematic model of ROMK. A: the proposed subunit structure with the 2nd transmembrane helices, M2, lining the pore. B: two of the four subunits forming the channel illustrating the pore helix in the M1-M2 linker.

FIG. 14

A schematic model of a single ROMK subunit in the channel tetramer showing the amino-terminal extentions forming ROMK1 and ROMK3, as well as the amino acids that mediate regulation of this channel.

FIG. 15

Expression of ROMK in the rat kidney. A: in situ hybridization showing the wide expression of ROMK in cortex, mainly in medullary rays, and in outer medulla. B: Western blot showing the apical expression of ROMK in the medullary thick ascending limb (MTAL).

FIG. 16

Distribution of ROMK isoforms along the nephron.

FIG. 17

A and B are computer-generated models of the structure of the cytoplasmic carboxy terminus of ROMK produced by threading ROMK using Kir-Bac1.1 as a template (Swiss-Model). A: the residues that have been identified to line the cytoplasmic pore and involved in interaction with cations mediating inward rectification. B: the carboxy-terminal serine residues that are phosphorylated by protein kinase A. C: localization of the equivalent residues on KirBac1.1 that form the pH sensor on ROMK.

FIG. 18

Overview of the factors and mechanisms of regulation of ROMK.

FIG. 19

Schematic model of the TAL illustrating the transporters that cause Bartter’s syndrome.

FIG 20

Mutations in ROMK that are associated with Bartter’s syndrome.

FIG. 21

Localization of 6-TM channels in the apical membrane of the proximal tubule. Also shown is the single TM subunit KCNE1 (MinK) that forms the KVLQT1 channel with the 6-TM subunit KCNQ1. These K⁺ channels are thought to stabilize the apical membrane potential that supports entry of amino acids and glucose via their respective Na⁺-coupled electrogenic transporters.

FIG. 22

Localization of 6-TM channels in the apical and basolateral membranes of distal tubular cells. These channels may help stabilize the apical membrane potential when Na⁺ entry (via the epithelial channel, ENaC) activity is increased by aldosterone (Aldo).