A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type Ca²⁺ channels.

Ca_v3 / T-type Ca²⁺ channels are dynamically regulated by intracellular Ca²⁺ ions, which inhibit Ca_v3 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 Ca_v3 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 NaN₃ treatment further support the involvement of a phosphorylation mechanism. Contrasting with Ca_v1 and Ca_v2 Ca²⁺ channels, the Ca²⁺-dependent modulation of Ca_v3 channels appears to be independent of calmodulin, calcineurin and endocytic pathways. Similar findings were obtained for the native T-type Ca²⁺ current recorded in rat thalamic neurons of the central medial nucleus. Overall, our data reveal a new Ca²⁺ sensitive phosphorylation-dependent mechanism regulating Ca_v3 channels, with potentially important physiological implications for the multiple cell functions controlled by T-type Ca²⁺ channels.

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