The role of IP3R and TRPC3 channels in vasoconstriction and hypertension

Abstract Hypertension is a major global health concern and a leading risk factor for cardiovascular diseases, including stroke, myocardial infarction, and heart failure. A hallmark of hypertension is elevated total peripheral vascular resistance, often driven by sustained and abnormal vasoconstriction. Calcium ions (Ca²⁺) play a central role in vascular smooth muscle cell (VSMC) contraction, and their intracellular concentration is tightly regulated by multiple signaling pathways. Among these, the inositol 1,4,5-trisphosphate receptor (IP 3 R) and the transient receptor potential canonical type 3 (TRPC3) channel are critical mediators of Ca²⁺ signaling. IP 3 R activation triggers Ca²⁺ release from the endoplasmic reticulum, while TRPC3 channels facilitate Ca²⁺ and Na⁺ influx across the plasma membrane. Several studies have shown that both IP 3 Rs and TRPC3 channels are upregulated in hypertensive animal models. Human studies have also demonstrated elevated TRPC3 expression in the context of pulmonary arterial hypertension (PAH). This review provides a comprehensive overview of the structural domains and membrane microdomains that facilitate IP 3 R–TRPC3 coupling and Ca²⁺ influx. IP₃ and endothelin-1 stimulate TRPC3 channels and promote their molecular coupling to IP 3 Rs, leading to activation of nonselective cation currents in artery myocytes. Increased expression and/or activity of IP 3 Rs and TRPC3 channels amplifies this signaling, contributing to the increased vascular tone characteristic of the hypertensive state. Understanding the molecular interplay between IP 3 Rs and TRPC3 channels offers new insight into the dysregulated Ca²⁺ signaling underlying hypertension. Targeting this coupling mechanism may represent a novel therapeutic strategy to restore vascular homeostasis and reduce blood pressure in affected individuals.