Chapter 13 Intracellular Regulation of Inwardly Rectifying Potassium Channels

Intracellular regulation of inward rectifier K+ channels

“…Upregulation by PIP 2 interaction may antagonize ATP-dependent closure in K ATP channels [5]. At the same time, mutated Kir2.1 channels can recover from pH-dependent closure in the presence of Mg-ATP, which is thought to act via PIP 2 kinase [54]. Thus, it seems likely that the stimulating effect of PIP 2 counteracts the inactivated states induced by ATP in Kir6.2 channels and by H + in mutated Kir2.1 channels.…”

“…In contrast to indirect regulation by protein kinases, the effect of intracellular pH on Kir1.1 and Kir4.1 channels is mediated by the channel protein itself [21,54,57]. Intracellular acidification closes Kir1.1 and Kir4.1 channels rapidly and with a steep pH dependence (Fig.…”

“…It is driven by protonation/deprotonation of the amino group of a lysine residue at position 80 in Kir1.1 (position 76 in Kir4.1) [21,54]. In contrast to the general chemical behaviour of lysine residues, this particular lysine residue is not protonated at neutral pH values.…”

“…This class of ion channel plays a key role in cell physiology: Kir channels maintain the resting potential near the K + reversal potential (E K ), set a threshold for excitation that depends on both membrane voltage (E) and the regulatory state of the channels [31], and they control K + homeostasis and K + secretion [68]. The biophysical properties behind these physiological functions are the channels' characteristic inward rectification [18] and their strong modulation by intracellular factors and second messengers [50,53,54]. The best known examples of the physiological importance of Kir regulation are as follows: the ATP dependence of Kir6.X (K ATP ) channels in the control of insulin secretion [2,3] and the determination of myocardial resistance to hypoxia [7,9]; the regulation of Kir3.X (GIRK) K + channels by Gproteins to account for the vagal control of heart rate [41,70]; the regulation of Kir1.X (ROMK) channels by [K + ] and pH, which controls K + secretion in kidney [67]; and the regulation of Kir4.1 channels in glial cells [37] and the inner ear [29], controlling K + homeostasis and excitability.…”