TRPM4 channels in smooth muscle function

Abstract

The melastatin (M) Transient Receptor Potential (TRP) channel TRPM4 is selective for monovalent cations and is activated by high levels of intracellular Ca2+. TRPM4 is broadly distributed and may be involved in numerous functions, including electrical conduction in the heart, respiratory rhythm, immune response, and secretion of insulin by pancreatic β cells. The significance of TRPM4 in smooth muscle cell function is reviewed here. Several studies indicate that TRPM4 channels are critically important for pressure-induced cerebral arterial myocyte depolarization and myogenic vasoconstriction as well as autoregulation of cerebral blood flow. Regulation of TRPM4 activity in arterial smooth muscle cells is complex, and involves release of Ca2+ from the sarcoplasmic reticulum through inositol 1,4,5 trisphosphate receptors and translocation of TRPM4 channels to the plasma membrane in response to Protein Kinase Cδ. TRPM4 is also present in colonic, urinary bladder, aortic, interlobar pulmonary and renal artery, airway, and corpus cavernosum smooth muscle cells, but its significance and regulation in these tissues is less well-characterized.

Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

“…While the TRPM channels represent the largest family of TRP channels in quantity, only two members are expressed in vascular SMCs: TRPM4 and TRPM8 (360, 712, 1358). TRPM4 channels have been found throughout the vascular tree, and are present in myogenically active resistance arteries and large conduit arteries alike (360).…”

“…TRPM4 channels have been found throughout the vascular tree, and are present in myogenically active resistance arteries and large conduit arteries alike (360). As mentioned earlier, TRPM4 is impermeable to divalent cations; TRPM4 is instead responsible for Na + influx that causes membrane depolarization of SMCs (367).…”

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…It is noteworthy that translocation of the TRPM4 channels at the plasma membrane via a PKC-dependent pathway is key for the channel activation by calcium release through IP 3 R (Crnich et al, 2010;Garcia et al, 2011). Because activation of TRPM4 by a PKC-dependent pathway is involved in the myogenic response to increased intravascular pressure (Earley et al, 2004(Earley et al, , 2007Gonzales et al, 2010b), it has been hypothesized that the functional complex formed by IP 3 R, TRPM4, and PKC could play a role in the depolarization of VSMCs observed upon increase in intravascular pressure (Earley, 2013). However, neither the origin of IP 3 R activation by increased levels of IP 3 (Narayanan et al, 1994) nor the origin of PKC activation upon increase intravascular pressure has been elucidated (Earley, 2013).…”

“…Because activation of TRPM4 by a PKC-dependent pathway is involved in the myogenic response to increased intravascular pressure (Earley et al, 2004(Earley et al, , 2007Gonzales et al, 2010b), it has been hypothesized that the functional complex formed by IP 3 R, TRPM4, and PKC could play a role in the depolarization of VSMCs observed upon increase in intravascular pressure (Earley, 2013). However, neither the origin of IP 3 R activation by increased levels of IP 3 (Narayanan et al, 1994) nor the origin of PKC activation upon increase intravascular pressure has been elucidated (Earley, 2013). Mechanical activation of G q receptors by increased intravascular pressure has been suggested (Mederos y Schnitzler et al, 2008;Brayden et al, 2013) and could reconcile the ideas that Regulation of Cellular Communication in Blood Vessel Wall both PKC and IP 3 R are activated during increased intravascular pressure, which would, respectively, result in relocation of the TRPM4 at the plasma membrane and in its activation.…”

“…Mechanical activation of G q receptors by increased intravascular pressure has been suggested (Mederos y Schnitzler et al, 2008;Brayden et al, 2013) and could reconcile the ideas that Regulation of Cellular Communication in Blood Vessel Wall both PKC and IP 3 R are activated during increased intravascular pressure, which would, respectively, result in relocation of the TRPM4 at the plasma membrane and in its activation. Further investigation is needed, because activation of G q receptors upon increased intravascular pressure is controversial (Anfinogenova et al, 2011;Earley, 2013).…”