Ca_V1.2 and Ca_V1.3 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 β cell physiology and pathophysiology. β 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 β cell apoptosis. The present study was aimed at revealing the subtypes of Ca_V1 channels hyperactivated by T1D serum as well as the biophysical mechanisms responsible for T1D serum-induced hyperactivation of β cell Ca_V1 channels. Patch-clamp recordings and single-cell RT-PCR analysis were performed in pancreatic β cells from Ca_V1 channel knockout and corresponding control mice. We now show that functional Ca_V1.3 channels are expressed in a subgroup of islet β cells from Ca_V1.2 knockout mice (Ca_V1.2^-/-). T1D serum enhanced whole-cell Ca_V currents in islet β cells from Ca_V1.3 knockout mice (Ca_V1.3^-/-). T1D serum increased the open probability and number of functional unitary Ca_V1 channels in Ca_V1.2^-/- and Ca_V1.3^-/- β cells. These data demonstrate that T1D serum hyperactivates both Ca_V1.2 and Ca_V1.3 channels by increasing their conductivity and number. These findings suggest Ca_V1.2 and Ca_V1.3 channels as potential targets for anti-diabetes therapy.