Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels

Department of Pharmacology, University of Iowa, Iowa City, Iowa This review addresses the localized regulation of voltage-gated ion channels by phosphorylation. Comprehensive data on channel regulation by associated protein kinases, phosphatases, and related regulatory proteins are mainly available for voltage-gated Ca 2+ channels, which form the main focus of this review. Other voltage-gated ion channels and especially K v 7.1-3 (KCNQ1-3), the large- and small-conductance Ca 2+ -activated K + channels BK and SK2, and the inward-rectifying K + channels K ir 3 have also been studied to quite some extent and will be included. Regulation of the L-type Ca 2+ channel Ca v 1.2 by PKA has been studied most thoroughly as it underlies the cardiac fight-or-flight response. A prototypical Ca v 1.2 signaling complex containing the β 2 adrenergic receptor, the heterotrimeric G protein G s , adenylyl cyclase, and PKA has been identified that supports highly localized via cAMP. The type 2 ryanodine receptor as well as AMPA- and NMDA-type glutamate receptors are in close proximity to Ca v 1.2 in cardiomyocytes and neurons, respectively, yet independently anchor PKA, CaMKII, and the serine/threonine phosphatases PP1, PP2A, and PP2B, as is discussed in detail. Descriptions of the structural and functional aspects of the interactions of PKA, PKC, CaMKII, Src, and various phosphatases with Ca v 1.2 will include comparisons with analogous interactions with other channels such as the ryanodine receptor or ionotropic glutamate receptors. Regulation of Na + and K + channel phosphorylation complexes will be discussed in separate papers. This review is thus intended for readers interested in ion channel regulation or in localization of kinases, phosphatases, and their upstream regulators.