TRPC1 downregulation enhances catecholamine secretion in adrenal chromaffin cells under metabolic syndrome conditions

Abstract

Increased catecholamine (CA) secretion from the adrenal medulla has been observed in patients with Metabolic Syndrome (MetS) and in animal models. Neuroendocrine adrenal medulla chromaffin cells (AMCCs) release catecholamines in response to Ca²⁺ influx through calcium channels. This study investigates the role of TRPC channels in mediating calcium influx in AMCCs under MetS conditions. NGF-induced PC12 cells were cultured in a MetS-mimicking (MMetS) medium, and CA secretion, as well as TRPC1 and TRPC5 expression, were assessed. The role of TRPC1 was further explored using siRNA-mediated knockdown in PC12 cells. Additionally, wild-type (WT) and TRPC1 knockout (TRPC1^−/−) mice on a high-fat diet (HFD) were used to evaluate in vivo CA secretion and TRPC channel expression. Intracellular [Ca²⁺] levels in isolated chromaffin cells from mice were measured using live-cell imaging. CA secretion was significantly increased in PC12 cells cultured in the MMetS medium, which was accompanied by downregulation of TRPC1 and upregulation of TRPC5. TRPC1 knockdown via siRNA further increased TRPC5 mRNA levels and CA secretion in MMetS-treated PC12 cells. In MetS mice, TRPC1 deletion led to enhanced CA secretion, elevated body weight, cholesterol levels, and blood pressure compared to WT mice. TRPC1 deletion also potentiated TRPC-mediated calcium influx in chromaffin cells and further upregulated TRPC5 expression under MetS conditions. These findings suggest that TRPC1 downregulation enhances intracellular calcium signaling and CA secretion by reducing its inhibitory effect on TRPC5, providing insights for potential therapeutic strategies in MetS-related pathophysiology.