CaMKIIδ-TRPC6 Activates an RyR-BK(Ca) Feedback Axis in Aging Arteries.

CaMKIIδ-dependent TRPC6 membrane externalization in resistance-sized small mesenteric artery VSMCs is linked to enhanced RyR Ca2+ sparks and BKCa currents specifically in old (12–14 months) mice.

• Why it matters: Aging alters blood pressure control, but how TRPC6-driven Ca2+ entry reshapes sarcoplasmic reticulum Ca2+ sparks and BKCa feedback is unclear.
• What they did: VSMCs from young (3–4 months) and old mice were tested with TRPC6 inhibitors SH045 or SAR7334 and with smooth muscle-specific TRPC6 knockout mice, measuring RyR Ca2+ sparks, BKCa currents, and myogenic tone; CaMKIIδ signaling was probed pharmacologically and with a CaMKIIδ-targeting proteolysis-targeting chimera peptide degrader.
• The result: In old VSMCs, TRPC6 inhibition suppressed RyR-mediated Ca2+ spark generation, reduced BKCa currents, and increased arterial constriction, effects attributed to CaMKIIδ-mediated TRPC6 plasma membrane translocation and RyR activation.

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