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The β-cell is equipped with at least six voltage-gated Ca2+ (Cav) channel α1-subunits designated Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav2.3, and Cav3.1. These principal subunits, together with certain auxiliary subunits, assemble into different types of Cav channels conducting L-, P/Q-, N-, R-, and T-type Ca2+ currents, respectively. The β cell shares customary mechanisms of Cav channel regulation with other excitable cells, such as protein phosphorylation, Ca2+-dependent inactivation, and G protein modulation How ever, the β-cell displays some characteristic features to bring these mechanisms into play. In islet β-cells. Cav channels can be highly phosphorylated under basal conditions and thus marginally respond to further phosphorylation. In β-cell lines, Cav channels can be surrounded by tonically activated protein phosphatases dominating over protein kinases; thus their activity is dramatically enhanced by inhibition of protein phosphatases. During the last 10 years, we have revealed some novel mechanisms of β-cell Cav channel regulation under physiological and pathophysiological conditions, including the involvement of exocytotic proteins, inositol hexakisphosphate, and type 1 diabetic serum. This minireview highlights characteristic features of customary mechanisms of Cav channel regulation in β-cells and also reviews our studies on newly identified mechanisms of β-cell Cav channel regulation. [ABSTRACT FROM AUTHOR]

Hypoglycemic sulfonylureas such as glibenclamide have been widely used to treat type 2 diabetic patients for 40 yr, but controversy remains about their mode of action. The widely held view is that they promote rapid insulin exocytosis by binding to and blocking pancreatic β-cell ATP-dependent K[sup +] (K[sub ATP]) channels in the plasma membrane. This event stimulates Ca[sup 2+] influx and sets in motion the exocytotic release of insulin. However, recent reports show that >90% of glibenclamide-binding sites are localized intracellularly and that the drug can stimulate insulin release independently of changes in K[sub ATP] channels and cytoplasmic free Ca[sup 2+]. Also, glibenclamide specifically and progressively accumulates in islets in association with secretory granules and mitochondria and causes long-lasting insulin secretion. It has been proposed that nutrient insulin secretagogues stimulate insulin release by increasing formation of malonyl-CoA, which, by blocking carnitine palmitoyltransferase 1 (CPT-1), switches fatty acid (FA) catabolism to synthesis of PKC-activating lipids. We show that glibenclamide dose-dependently inhibits β-cell CPT-1 activity, consequently suppressing FA oxidation to the same extent as glucose in cultured fetal rat islets. This is associated with enhanced diacylglycerol (DAG) formation, PKC activation, and K[sub ATP]-independent glibenclamide-stimulated insulin exocytosis. The fat oxidation inhibitor etomoxir stimulated K[sub ATP]-independent insulin secretion to the same extent as glibenclamide, and the action of both drugs was not additive. We propose a mechanism in which inhibition of CPT-1 activity by glibenclamide switches β-cell FA metabolism to DAG synthesis and subsequent PKC-dependent and K[sub ATP]-independent insulin exocytosis. We suggest that chronic CPT inhibition, through the progressive islet accumulation of glibenclamide, may explain the prolonged stimulation of insulin secretion in some diabetic... [ABSTRACT FROM AUTHOR]