Molecular and cellular basis of small--and intermediate-conductance, calcium-activated potassium channel function in the brain

Abstract

Small conductance calcium-activated potassium (SK or K(Ca)2) channels link intracellular calcium transients to membrane potential changes. SK channel subtypes present different pharmacology and distribution in the nervous system. The selective blocker apamin, SK enhancers and mice lacking specific SK channel subunits have revealed multifaceted functions of these channels in neurons, glia and cerebral blood vessels. SK channels regulate neuronal firing by contributing to the afterhyperpolarization following action potentials and mediating I(AHP), and partake in a calcium-mediated feedback loop with NMDA receptors, controlling the threshold for induction of hippocampal long-term potentiation. The function of distinct SK channel subtypes in different neurons often results from their specific coupling to different calcium sources. The prominent role of SK channels in the modulation of excitability and synaptic function of limbic, dopaminergic and cerebellar neurons hints at their possible involvement in neuronal dysfunction, either as part of the causal mechanism or as potential therapeutic targets.

Figure 1

Sequence alignment of the human small conductance Ca²⁺-activated K⁺ channels hSK1, hSK2 and hSK3. The putative transmembrane spanning regions, S1–S6, are boxed in gray. The pore region (P-Region) is boxed in turquoise. The calmodulin-binding domain (CaMBD) is indicated by black bars. Amino acids corresponding to phosphorylation consensus sequences for the cyclic AMP- and cyclic GMP-dependent kinases (PKA and PKG) are displayed in red, for protein kinase C (PKC) in blue; and for casein kinase 2 (CK2) boxed in orange. Only intracellular phosphorylation consensus sequences have been labeled for PKA, PKG and PKC, while both intra- and extracellular ones have been highlighted for CK2 because of its potential action as an endo- and ectokinase [263]. Phosphorylation consensus sites have been mapped using the Prosite database: for PKA/PKG: PS00004: [RK](2)-x-[ST]; for PKC: PS00005: [ST]-x-[RK]; for CK2: PS00006: [ST]-x(2)-[DE].