TRP-ing up heart and vessels: Canonical transient receptor potential channels and cardiovascular disease

Transient receptor potential channels are a large superfamily of non-selective and non-voltage-gated ion channels that convey signaling information linked to a broad range of sensory inputs. In the cardiovascular system, the canonical transient receptor potential (TRPC) family has been particularly found to play a role in vascular and cardiac disease, responding to neurohormonal and mechanical load stimulation. TRPC1, TRPC3, and TRPC6 are often upregulated in models of cardiovascular disease, and their inhibition ameliorates the associated pathophysiology. Studies in gene deletion models and overexpression models of wild-type and dominant-negative proteins supports a direct role of these channels, which likely act together as heterotetramers to influence signaling. Recent evidence has further revealed the importance of protein kinase G phosphorylation as a mechanism to suppress TRPC6 channel current and dependent signaling in vascular and cardiac myocytes. This suggests a novel mechanism underlying benefits of drugs such as sildenafil, a phosphodiesterase type 5 inhibitor, nitrates, and atrial natriuretic peptides. This review describes new evidence supporting a pathophysiologic role of these three TRPC channels, and the potential utility of inhibition strategies to treat cardiovascular disease.