Modulation of ION Channels by Protein Phosphorylation and Dephosphorylation

Abstract

Modulation of the properties of membrane ion channels is of fundamental importance for the regulation of neuronal electrical activity and of higher neural functions. Among the many potential molecular mechanisms for modulating the activity of membrane proteins such as ion channels, protein phosphorylation has been chosen by cells to play a particularly prominent part. This is not surprising given the central role of protein phosphorylation in a wide variety of cellular, metabolic, and signaling processes (26, 27, 48). As summarized here, regulation by phosphorylation is not restricted to one or another class of ion channel; rather, many, and perhaps all, ion channels are subject to modulation by phosphorylation. Similarly, a number of different protein kinase signaling pathways can participate in the regulation of ion channel properties, and it is not unusual to find that a particular channel is modulated by several different protein kinases, each influencing channel activity in a unique way. Finally, the biophysical mechanisms of modulation also exhibit a striking diversity that ranges from changes in desensitization rates to shifts in the voltage dependence and kinetics of channel activation and inactivation. The convergence of channel molecular biology with patch-clamp technology has been spectacularly productive, even allowing the identification of particular amino acid residues in ion channel proteins that participate in specific modulatory changes in channel biophysical properties. This task is far from complete, and no doubt there remain surprises in store for us, but nevertheless it is appropriate to ask where we go from here. One important direction will be to relate functional modulation, produced by phosphorylation, to changes in the three-dimensional structure of the ion channel protein. Unfortunately, structural studies of membrane proteins are extremely difficult, and to date there is no high resolution structure available for any ion channel protein. A complementary strategy that is more feasible with current technology is to investigate the ways in which channel modulation contributes to the regulation of cellular physiology. Novel computational approaches are being brought to bear on this complex issue, and their combination with channel molecular biology and biophysics should significantly advance our understanding of molecular mechanisms of neuronal plasticity.

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

“…Protein phosphorylation is an important biological process that is a possible mechanism for the regulation of the activities of ion channels and a wide variety of cellular functions [34]. In addition to being regulated by various nucleotides, the activity of the K ATP channel can be further modulated by phosphorylation events induced by activated protein kinase A and protein kinase C [21,22].…”

Identification and cloning of TWIK‐originated similarity sequence (TOSS): a novel human 2‐pore K+ channel principal subunit

“…Phosphorylation and dephosphorylation of speci¢c amino acid residues is often an important mechanism of ion channel regulation [14]. A consensus protein kinase C phosphorylation site is identi¢ed in hTOSS at position 158^160 in the amino acid sequence.…”

Imaging of intracellular calcium during desensitization of nicotinic acetylcholine receptors of rat chromaffin cells

“…Although the long lasting nature of [Ca 2+ ] i increase by nicotine is compatible with the ®rst hypothesis, initially put forward by Manthey (1966), the second possibility accords with recent biochemical and electrophysiological observations. In fact, molecular biology studies have shown that desensitization is an intrinsic property of ligand-gated ionotropic receptors (see review by Lena & Changeux, 1993) and that is can be modulated by intracellular second messengers via phosphorylation of certain receptor subunits (Levitan, 1994). Several studies have focussed on protein kinase C (PKC) as the [Ca 2+ ] i activated e ector which modulates desensitization of nicotinic AChRs.…”