Regulation of Cerebral Artery Smooth Muscle Membrane Potential by Ca²⁺‐Activated Cation Channels

Abstract

Arterial tone is dependent on the depolarizing and hyperpolarizing currents regulating membrane potential and governing the influx of Ca2+ needed for smooth muscle contraction. Several ion channels have been proposed to contribute to membrane depolarization, but the underlying molecular mechanisms are not fully understood. In this review, we will discuss the historical and physiological significance of the Ca2+-activated cation channel, TRPM4, in regulating membrane potential of cerebral artery smooth muscle cells. As a member of the recently described transient receptor potential super family of ion channels, TRPM4 possesses the biophysical properties and upstream cellular signaling and regulatory pathways that establish it as a major physiological player in smooth muscle membrane depolarization.

Novel regulatory mechanism in human urinary bladder: central role of transient receptor potential melastatin 4 channels in detrusor smooth muscle function

“…On the other hand, activation of TRPM4 channels would favor an increase in Na ϩ influx, causing membrane depolarization (11). Therefore, unlike K ϩ channels, which are responsible primarily for membrane hyperpolarization, TRPM4 channels contribute to the depolarization component of the ionic currents in excitable cells (15,17,29,30).…”

“…Given the greater driving force for Na ϩ than K ϩ under physiological conditions, pharmacological inhibition of TRPM4 channels can reduce the net Na ϩ influx to promote membrane potential hyperpolarization (15,16). On the other hand, activation of TRPM4 channels would favor an increase in Na ϩ influx, causing membrane depolarization (11).…”

“…Activation of TRPM4 channels causes cell membrane depolarization via Na ϩ influx, which in turn activates L-type voltage-gated Ca 2ϩ (Ca V ) channels (11). Alternatively, inhibition of TRPM4 channels promotes substantial cell hyperpolarization and smooth muscle relaxation (15,16). Because of these unique channel properties, selective modulation of TRPM4 channels may have profound effects on cell excitability and may be an attractive, novel approach for the pharmacological treatment of various conditions, including OAB.…”

Sodium‐activated potassium channels moderate excitability in vascular smooth muscle

“…Diacylglycerol activates protein kinase C and may play additional roles in activating Ca 2+ entry. GqPCR receptor stimulation in ASM cells also leads to the activation of nonselective cation channels such as TRPM4 (Gonzales & Earley, ). TRPM4 is permeable mainly to monovalent cations and its activation will further depolarize ASM cells, which in turn will activate voltage‐dependent Ca 2+ channels, allowing additional Ca 2+ influx.…”

TRPM4 channels in smooth muscle function

“…For example, when intracellular Ca 2+ is maintained at 10 μM, TRPM4 currents exhibit time-dependent decay, with currents completely inactivated in most cells within 120 s in HEK and A7r5 cell expression systems [21, 22] and naïve cerebral artery smooth muscle cells [20]. Inhibition of phospholipase C (PLC) or inclusion of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) in the intracellular solution prevents time-dependent decrease of TRPM4 currents [23, 24].…”