Abstract
Transient receptor potential melastatin-4 (TRPM4) is activated by an increase in intracellular Ca2+ concentration and is expressed on smooth muscle cells (SMCs). It is implicated in the myogenic constriction of cerebral arteries. We hypothesized that TRPM4 has a general role in intracellular Ca2+ signal amplification in a wide range of blood vessels. TRPM4 function was tested with the TRPM4 antagonist 9-phenanthrol and the TRPM4 activator A23187 on the cardiovascular responses of the rat, in vivo and in isolated basilar, mesenteric, and skeletal muscle arteries. TRPM4 inhibition by 9-phenanthrol resulted in hypotension and a decreased heart rate in the rat. TRPM4 inhibition completely antagonized myogenic tone development and norepinephrine-evoked vasoconstriction, and depolarization (high extracellular KCl concentration) evoked vasoconstriction in a wide range of peripheral arteries. Vasorelaxation caused by TRPM4 inhibition was accompanied by a significant decrease in intracellular Ca2+ concentration, suggesting an inhibition of Ca2+ signal amplification. Immunohistochemistry confirmed TRPM4 expression in the smooth muscle cells of the peripheral arteries. Finally, TRPM4 activation by the Ca2+ ionophore A23187 was competitively inhibited by 9-phenanthrol. In summary, TRPM4 was identified as an essential Ca2+-amplifying channel in peripheral arteries, contributing to both myogenic tone and agonist responses. These results suggest an important role for TRPM4 in the circulation. The modulation of TRPM4 activity may be a therapeutic target for hypertension. Furthermore, the Ca2+ ionophore A23187 was identified as the first high-affinity (nanomolar) direct activator of TRPM4, acting on the 9-phenanthrol binding site.
Highlights
Members of the transient receptor potential melastatin (TRPM) channel subfamily are expressed on vascular smooth muscle cells, and are involved in vascular smooth muscle function [1]
The effect of Transient receptor potential melastatin-4 (TRPM4) inhibition was investigated by i. v. administration of 9-phenanthrol into the jugular veins of rats. 9-Phenanthrol caused a dose-dependent, transient decrease in blood pressure (Figure 1A)
The current study was designed to investigate the contribution of TRPM4 to vascular constriction in various isolated arteries and in the systemic circulation
Summary
Members of the transient receptor potential melastatin (TRPM) channel subfamily are expressed on vascular smooth muscle cells, and are involved in vascular smooth muscle function [1]. The TRPM4 is a nonselective cation channel [2] that is known to play a critical role in the development of cerebrovascular myogenic tone [3,4,5]. Myogenic tone of the cerebral arteries is essential for the autoregulation of intracranial blood flow, and in vivo suppression of TRPM4 leads to the impairment of this autoregulation in a rat model [6]. TRPM4 is activated by the increase in the intracellular Ca2+ concentration and is impermeable to Ca2+ [7]. TRPM4 elicits rapid desensitization to intracellular Ca2+, which is inhibited by phosphatidylinositol-4,5-bisphosphate [8,9]. Protein kinase C (PKC) modulates its Ca2+ sensitivity and activity through phosphorylation in vascular smooth muscle cells [3,10]
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