Supramolecular Assemblies and Localized Regulation of Voltage-Gated Ion Channels

Abstract

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 Ca2+ channels, which form the main focus of this review. Other voltage-gated ion channels and especially Kv7.1-3 (KCNQ1-3), the large- and small-conductance Ca2+-activated K+ channels BK and SK2, and the inward-rectifying K+ channels Kir3 have also been studied to quite some extent and will be included. Regulation of the L-type Ca2+ channel Cav1.2 by PKA has been studied most thoroughly as it underlies the cardiac fight-or-flight response. A prototypical Cav1.2 signaling complex containing the β2 adrenergic receptor, the heterotrimeric G protein Gs, 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 Cav1.2 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 Cav1.2 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.

Ca2+-independent Activation of Ca2+/Calmodulin-dependent Protein Kinase II Bound to the C-terminal Domain of CaV2.1 Calcium Channels

“…Although both proteins bind CaM and CaMKII to nearby sites in their C-terminal domains, the regulatory consequences are quite different. Binding of Ca 2ϩ / CaM to Ca V 2.1 channels causes facilitation followed by inactivation, whereas binding to Ca V 1.2 channels causes only Ca 2ϩ -dependent inactivation (9,51). Binding of CaMKII to Ca V 2.1 channels enhances their activity and their facilitation, whereas phosphorylation of Ca V 1.2 channels by CaMKII bound to the C-terminal domain and/or the Ca V ␤2 subunit is required for facilitation of their activity (9,37,52,53).…”

Identification of Glycosylation Sites Essential for Surface Expression of the CaVα2δ1 Subunit and Modulation of the Cardiac CaV1.2 Channel Activity

“…High voltage-activated Ca V 1.2 channels are hetero-oligomers composed of the main pore-forming Ca V ␣1 subunit non-covalently bound to the cytoplasmic Ca V ␤ auxiliary subunit, the EF-hand protein calmodulin (constitutively bound to the C terminus of Ca V ␣1), and the Ca V ␣2␦ subunit (11)(12)(13)(14)(15)(16). The full complement of auxiliary subunits is required to produce high voltage-activated Ca V 1.2 channels with the properties of the native channels.…”

S-Glutathionylation of Ion Channels: Insights into the Regulation of Channel Functions, Thiol Modification Crosstalk, and Mechanosensing

“…Post-translational modifications (PTMs) are important mechanisms regulating ion channel functions. One of the classical PTM is protein phosphorylation, and a large number of ion channels are found to be regulated by phosphorylation through PKA, PKC, and other protein kinases (30,57,109,112,113,139). A variety of different types of PTMs (e.g., Ubiquitylation, SUMOylation, O-glycosylation/ O-GlcNAcylation, etc.)…”