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

L-type Ca channels govern smooth muscle [Ca ] 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 Ca channels are additionally mechanosensitive. In this context, this study defined whether and by what mechanisms pressure stimuli modulate L-type Ca 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 Ca 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 [Ca ] 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 Ca channels are indeed mechanosensitive. Cumulatively, our results suggest that there is more to L-type Ca 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.