Deletion of α 2 δ-1 Calcium Channel Subunit Reduces Calcium Influx and Alters the Electrical Activity of Mouse Chromaffin Cells
Biophysical Journal(2017)
摘要
Calcium influx through high voltage gated calcium channels (HVCC) shapes the electrical activity and controls catecholamine release of mouse chromaffin cells (MCCs). HVCC are multi-subunit protein complexes composed of the pore forming α1 and auxiliary α2δ and β subunits. α2δ is a key regulator of HVCCs membrane incorporation and function. Here we show that genetic deletion of α2δ-1, the dominant α2δ isoform in MCCs, reduces the L-, R- and P/Q-N-type calcium currents by ∼50% without affecting the current kinetics. This dramatically altered the electrical activity of α2δ-1-/- MCCs. Only 40% of α2δ-1-/- MCCs showed spontaneous firing compared to 90% in WT cells. The action potentials (AP) had a smaller half width as the maximum rise and decay slopes were significantly higher in α2δ-1-/- cells compared to WT. During ramp current injection the inter-spike interval was similar but, the AP amplitude decreased faster in α2δ-1-/- MCCs. Upon incremental step current injections, the WT MCCs responded with increasing firing frequency whereas α2δ-1-/- MCCs had a high firing frequency independent of stimulation. While smaller calcium influx explains the shortening of the AP in α2δ-1-/- MCCs, the altered firing frequency is caused by reduced functional coupling between HVCC and calcium-dependent potassium channels (BK and SK). The extracellular application of 20µM EGTA-AM resulted in a stronger reduction of calcium-dependent potassium conductance in α2δ-1-/- MCCs compared to WT. Taken together, our data demonstrate that α2δ-1 loss-of-function strongly affects calcium influx and electrical activity in MCCs. To assess the physiological relevance of our findings, we are currently quantifying the effect of α2δ-1 deletion on MCCs hormone release.
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关键词
calcium channel subunit,calcium channel,calcium influx
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