CaV1.2 and CaV1.3 channel hyperactivation in mouse islet β cells exposed to type 1 diabetic serum

The voltage-gated Ca2+ (Ca-V) channel acts as a key player in beta cell physiology and pathophysiology. beta cell Ca-V channels undergo hyperactivation subsequent to exposure to type 1 diabetic (T1D) serum resulting in increased cytosolic free Ca2+ concentration and thereby Ca2+-triggered beta cell apoptosis. The present study was aimed at revealing the subtypes of Ca(V)1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of beta cell Ca(V)1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic beta cells from Ca(V)1 channel knockout and corresponding control mice. We now show that functional Ca(V)1.3 channels are expressed in a subgroup of islet beta cells from Ca(V)1.2 knockout mice (Ca(V)1.2(-/-)). T1D serum enhanced whole-cell Ca-V currents in islet beta cells from Ca(V)1.3 knockout mice (Ca(V)1.3(-/-)). T1D serum increased the open probability and number of functional unitary Ca(V)1 channels in Ca(V)1.2(-/-) and Ca(V)1.3(-/-) beta cells. These data demonstrate that T1D serum hyperactivates both Ca(V)1.2 and Ca(V)1.3 channels by increasing their conductivity and number. These findings suggest Ca(V)1.2 and Ca(V)1.3 channels as potential targets for anti-diabetes therapy.