Sorbs2 Modulation of BK Channels in Arterial Myocytes: Implications for Diabetes

Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels (e.g.hyperglycemia).This disease state often leads to vascular complications (e.g.impaired vasodilation) that significantly contribute to its morbidity and mortality.Despite extensive research in this area, molecular and cellular mechanisms underlying vascular dysfunction during diabetic hyperglycemia remain to be fully elucidated.A study by Sun et al. 1 in the current issue of Circulation Research significantly expands our understanding of these mechanisms by revealing an intriguing role for the protein Sorbin and SH3 domain-containing protein 2 (Sorbs2) in the chain of events that contributes to vascular complications during diabetes.Arterial myocyte excitability and contractile state are modulated by an impressive collection of ion channels.These ion channels provide exquisite control of arterial myocyte membrane potential and the magnitude of changes in intracellular Ca 2+ concentration ([Ca 2+ ] i ).Accordingly, membrane depolarization, triggered by activation of activation of TRPC6 2 , TRPM4 3 , or TRPP1 (PKD2) 4 channels, activates Ca V 1.2 channels 5 .Activation of a single or a small cluster of Ca V 1.2 channels results in a local increase in intracellular Ca 2+ concentration ([Ca 2+ ] i ) termed a "Ca V 1.2 sparklet" 6 .Spatial and temporal summation of multiple Ca V 1.2 sparklets leads to a global increase in [Ca 2+ ] i that triggers muscle contraction.One key route of negative feedback regulation of this mechanism in arterial myocytes is the activation of large conductance Ca 2+ -activated K + (BK) channels 7 .In arterial myocytes, BK channels are composed of pore-forming α subunits and accessory β1 subunits.The BK β1 subunit flanks the BK α subunit to increase the sensitivity of BK channels to [Ca 2+ ] i .The BK β1 subunit accomplishes this primarily by stabilizing the active configuration of the voltage sensor and augmenting the effect of calcium binding at the RCK1 and Ca 2+ bowl sites located in the BK α subunit on channel opening.Intriguingly, loss or downregulation of sarcolemmal β1 is a hallmark of hypertension and diabetic vascular pathologies 8 .