A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type Ca channels.

Ca3 / T-type Ca channels are dynamically regulated by intracellular Ca ions, which inhibit Ca3 availability. Here, we demonstrate that this inhibition becomes irreversible in the presence of non-hydrolysable ATP analogs, resulting in a strong hyperpolarizing shift in the steady-state inactivation of the residual Ca3 current. Importantly, the effect of these ATP analogs was prevented in the presence of intracellular BAPTA. Additional findings obtained using intracellular dialysis of inorganic phosphate and alkaline phosphatase or NaN treatment further support the involvement of a phosphorylation mechanism. Contrasting with Ca1 and Ca2 Ca channels, the Ca-dependent modulation of Ca3 channels appears to be independent of calmodulin, calcineurin and endocytic pathways. Similar findings were obtained for the native T-type Ca current recorded in rat thalamic neurons of the central medial nucleus. Overall, our data reveal a new Ca sensitive phosphorylation-dependent mechanism regulating Ca3 channels, with potentially important physiological implications for the multiple cell functions controlled by T-type Ca channels.