Abstract
Cav3 / T-type Ca2+ channels are dynamically regulated by intracellular Ca2+ ions, which inhibit Cav3 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 Cav3 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 Cav1 and Cav2 Ca2+ channels, the Ca2+-dependent modulation of Cav3 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 Cav3 channels, with potentially important physiological implications for the multiple cell functions controlled by T-type Ca2+ channels.
Highlights
Cav3 / T-type Ca2+ channels are dynamically regulated by intracellular Ca2+ ions, which inhibit Cav[3] availability
Our results demonstrate that this Cav3.3 current modulation does not depend on calmodulin, calcineurin or endocytosis of the channels but is regulated by a phosphorylation-dependent process
During stimulations applied at 1 Hz frequency, the Cav3.3 current decreased ~45% from its initial value after 40 seconds (p < 0.001, Fig. 1A,B) and this decrease was associated with faster inactivation kinetics (p < 0.001, Fig. 1C)
Summary
Cav3 / T-type Ca2+ channels are dynamically regulated by intracellular Ca2+ ions, which inhibit Cav[3] availability. VGCC activity is tightly regulated by multiple intracellular pathways, including Ca2+ ions, which provide an important feedback control of Ca2+ homeostasis[3,4]. The Cav[3] channels display unique electrophysiological features including a low-voltage-activated Ca2+ current, fast inactivation kinetics and a strong steady-state inactivation at physiological resting potentials[6,7]. These electrophysiological properties of T-type channels allow the generation of low-threshold spikes in neurons subsequent to transient membrane hyperpolarization[6,7]. Our findings strongly suggest the involvement of a novel Ca2+ / phosphorylation-dependent transduction pathway that finely adjusts the T-type channel properties necessary for proper physiological function
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