Interplay among distinct Ca²⁺ conductances drives Ca²⁺ sparks/spontaneous transient outward currents in rat cerebral arteries

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• 作者：Ahmed M. Hashad ; Neil Mazumdar ; Monica Romero ; Anders Nygren ; Kamran Bigdely‐Shamloo ; Osama F. Harraz ; Jose L. Puglisi ; Edward J. Vigmond ; Sean M. Wilson ; Donald G. Welsh
• 刊名：The Journal of Physiology
• 出版年：2017
• 出版时间：15 February 2017
• 年：2017
• 卷：595
• 期：4
• 页码：1111-1126
• 全文大小：1.6MB
• ISSN：1469-7793

文摘

Ca²⁺ sparks are generated in a voltage-dependent manner to initiate spontaneous transient outward currents (STOCs), events that moderate arterial constriction. In this study, we defined the mechanisms by which membrane depolarization increases Ca²⁺ sparks and subsequent STOC production. Using perforated patch clamp electrophysiology and rat cerebral arterial myocytes, we monitored STOCs in the presence and absence of agents that modulate Ca²⁺ entry. Beginning with Ca_V3.2 channel inhibition, Ni²⁺ was shown to decrease STOC frequency in cells held at hyperpolarized (−40 mV) but not depolarized (−20 mV) voltages. In contrast, nifedipine, a Ca_V1.2 inhibitor, markedly suppressed STOC frequency at −20 mV but not −40 mV. These findings aligned with the voltage-dependent profiles of L- and T-type Ca²⁺ channels. Furthermore, computational and experimental observations illustrated that Ca²⁺ spark production is intimately tied to the activity of both conductances. Intriguingly, this study observed residual STOC production at depolarized voltages that was independent of Ca_V1.2 and Ca_V3.2. This residual component was insensitive to TRPV4 channel modulation and was abolished by Na⁺/Ca²⁺ exchanger blockade. In summary, our work highlights that the voltage-dependent triggering of Ca²⁺ sparks/STOCs is not tied to a single conductance but rather reflects an interplay among multiple Ca²⁺ permeable pores with distinct electrophysiological properties. This integrated orchestration enables smooth muscle to grade Ca²⁺ spark/STOC production and thus precisely tune negative electrical feedback.