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

BACKGROUND: TRP (transient receptor potential) cation channels play a crucial role in maintaining normal blood pressure and flow. We hypothesize that, during aging, TRPC6 (transient receptor potential cation channel subfamily C member 6)–mediated Ca 2+ influx promotes sarcoplasmic reticulum Ca 2+ refilling and RyR (ryanodine receptor) Ca 2+ sparks, thereby activating BK Ca (large-conductance Ca 2+ -activated K + ) channels to limit myogenic arterial tone. METHODS: Using vascular smooth muscle cells (VSMCs) from resistance-sized small mesenteric arteries, we tested selective TRPC6 inhibitors (SH045 and SAR7334) and smooth muscle–specific TRPC6 knockout mice. Ca 2+ sparks, BK Ca currents, and myogenic tone were measured in young (3–4 months) and old (12–14 months) mice. CaMKIIδ (Ca 2+ /calmodulin-dependent protein kinase IIδ) signaling was assessed pharmacologically and with a proteolysis-targeting chimera peptide degrader targeting CaMKIIδ. RESULTS: Inhibiting TRPC6 with SH045 or SAR7334 suppressed RyR-mediated Ca 2+ spark generation in VSMCs from old mice but not young mice. Similar results were found in smooth muscle–specific TRPC6 knockout mice. SH045 or SAR7334 also suppressed BK Ca currents and elicited constriction in mesenteric arteries from old mice. These effects were due to increased translocation of TRPC6 channels to the VSMC plasma membrane, mediated by CaMKIIδ signaling. Using a proteolysis-targeting chimera peptide degrader targeting CaMKIIδ, we demonstrated the impact of CaMKIIδ on TRPC6 externalization and RyR activation in old VSMCs. CONCLUSIONS: Together, our findings identify age-dependent CaMKIIδ upregulation as a key regulator of TRPC6 membrane trafficking, thereby indirectly enhancing RyR-BKCa signaling through sarcoplasmic reticulum Ca 2+ handling and promoting VSMC hyperpolarization and vasodilation in aging.