Excitability of the smooth muscle plasma membrane underlies numerous processes necessary for life, including blood flow and blood pressure regulation, gastrointestinal mobility, and urinary bladder function. Smooth muscle membrane depolarization in response to mechanical, neuronal, or humoral signals opens voltage-dependent Ca2+ channels (VDCCs), allowing Ca2+ influx and activation of contractile pathways. However, the molecular mechanisms underlying this membrane potential depolarization remain obscure. Our findings show that the melastatin transient receptor potential (TRP) channel TRPM4 mediates depolarization and vasoconstriction in response to both intraluminal pressure and vasoconstrictor agonists, suggesting that TRPM4 is the central regulator of membrane potential in vascular smooth muscle cells. Thus, one of the major goals of our laboratory is to elucidate the signaling mechanisms that regulate TRPM4 channel activity in arterial myocytes. We are currently examining how intracellular Ca2+ dynamics, protein kinase C (PKC), phospholipase C (PLC) and membrane trafficking influence regulation of TRPM4 activity in cerebral artery myocytes. Studies examining how members of the canonical TRP subfamily, such as TRPC3 and TRPC6, influence TRPM4 activity are also underway.