Pressure Modulation of Vascular L‐type Calcium Channels: implications to the Myogenic Response

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L‐type Ca2+ channels govern smooth muscle [Ca2+] and myogenic tone development through mechanisms traditionally tied to voltage control. While essential, questions remain as to whether voltage is the sole regulatory influence or whether L‐type Ca2+ channels are additionally mechanosensitive. In this context, this study defined whether and by what mechanisms pressure stimuli modulate L‐type Ca2+ channels in rodent (rat & mouse) resistance arteries. Experiments extended from single smooth muscle cells (whole‐cell/single‐channel patch clamp; immunohistochemistry; proximity ligation assay) to intact arteries (pressure myography). Whole‐cell patch clamp electrophysiology revealed that pressure stimuli increased the L‐type Ca2+ current, a phenomenon that single channel analysis attributed to enhanced functional coupling. Subsequent work noted that pressure‐enhanced functional coupling is tied to: 1) PKC‐mediated cooperative gating; and 2) subunit trafficking to caveolae. Functional experiments, using 30 mM KCl to elicit a set depolarization (~‐40 mV), revealed that tone and cytosolic [Ca2+] responses were more pronounced in arteries pressurized to 80 rather than 20 mmHg. These functional results are in alignment with patch clamp observations and suggest that L‐type Ca2+ channels are indeed mechanosensitive. Cumulatively, our results suggest that there is more to L‐type Ca2+ channel regulation than voltage and that pressure sensitivity must be carefully weighed in the healthy and diseased setting. Work continues to precisely define the pressure‐sensitive signaling complexes within vascular smooth muscle.