Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone

Abstract

Johnson CD, Melanaphy D, Purse A, Stokesberry SA, Dickson P, Zholos AV. Transient receptor potential melastatin 8 channel involvement in the regulation of vascular tone. Am J Physiol Heart Circ Physiol 296: H1868 -H1877, 2009. First published April 10, 2009 doi:10.1152/ajpheart.01112.2008.-The transient receptor potential melastatin 8 (TRPM8) channel has been characterized as a cold and menthol receptor expressed in a subpopulation of sensory neurons but was recently identified in other tissues, including the respiratory tract, urinary system, and vasculature. Thus TRPM8 may play multiple functional roles, likely to be in a tissue-and activation statedependent manner. We examined the TRPM8 channel presence in large arteries from rats and the functional consequences of their activation. We also aimed to examine whether these channels contribute to control of conscious human skin blood flow. TRPM8 mRNA and protein were detected in rat tail, femoral and mesenteric arteries, and thoracic aorta. This was confirmed in single isolated vascular myocytes by immunocytochemistry. Isometric contraction studies on endothelium-denuded relaxed rat vessels found small contractions on application of the TRPM8-specific agonist menthol (300 M). However, both menthol and another agonist icilin (50 M) caused relaxation of vessels precontracted with KCl (60 mM) or the ␣-adrenoceptor agonist phenylephrine (2 M) and a reduction in sympathetic nerve-mediated contraction. These effects were antagonized by bromoenol lactone treatment, suggesting the involvement of Ca 2ϩ -independent phospholipase A 2 activation in TRPM8-mediated vasodilatation. In thoracic aorta with intact endothelium, menthol-induced inhibition of KCl-induced contraction was enhanced. This was unaltered by preincubation with either N -nitro-L-arginine methyl ester (L-NAME; 100 nM), a nitric oxide synthase inhibitor, or the ACh receptor antagonist atropine (1 M). Application of menthol (3% solution, topical application) to skin caused increased blood flow in conscious humans, as measured by laser Doppler fluximetry. Vasodilatation was markedly reduced or abolished by prior application of L-NAME (passive application, 10 mM) or atropine (iontophoretic application, 100 nM, 30 s at 70 A). We conclude that TRPM8 channels are present in rat artery vascular smooth muscle and on activation cause vasoconstriction or vasodilatation, dependent on previous vasomotor tone. TRPM8 channels may also contribute to human cutaneous vasculature control, likely with the involvement of additional neuronal mechanisms.human; rat; artery ION CHANNELS, ESPECIALLY Ca 2ϩ -permeable channels, are of central importance to the control of vascular tone as well as long-term phenotypic remodeling. In recent years, members of the transient receptor potential (TRP) superfamily of cation channels attracted considerable interest as novel nonvoltage gated Ca 2ϩ permeable cation channels, important determinants of vascular function and disease (2, 4, 5, 13). These channels can be constitutively active or acti...

Activation of Cold-Sensing Transient Receptor Potential Melastatin Subtype 8 Antagonizes Vasoconstriction and Hypertension Through Attenuating RhoA/Rho Kinase Pathway

“…8,27 TRPM8-deficient mice exhibit strikingly reduced avoidance of cold temperatures and lack behavioral response to cold-inducing icilin application.…”

“…5,6 TRPM8 is mainly localized in the sensory neurons, but its distribution in the fundus and adipose tissue has also been reported. 7 Johnson et al 8 demonstrated that menthol-induced TRPM8 activation regulates vascular tone. Mustafa et al 9 reported…”

Cardiovascular effects of monoterpenes: a review

“…In study performed by Johnson et al (2009), was demonstrated that menthol is able to cause a profound dilatation in human forearm cutaneous vessels. This effect appears to involve activation of muscarinic receptors and/ or production of nitric oxide.…”

“…reduced blood pressure and heart rate, and inhibited the hypertension induced by L-NAME (Aydin et al, 2007). However, in isolated rat aorta, although Aydin et al (2007) did not observe any significant effect of carvacrol, PeixotoNeves et al (2010) demonstrated that this monoterpene induced an endothelium-independent relaxation, possibly cholinergic/nitric oxide pathways (Johnson et al, 2009) and mediated by activation of transient receptor potential melastatin 8 (TRPM8) (Venkatachalam & Montell, 2007;Johnson et al, 2009).…”

Dose-Dependent Cytotoxic Effects of Menthol on Human Malignant Melanoma A-375 Cells: Correlation with TRPM8 Transcript Expression

“…Transient receptor potential melastatin 8 (TRPM8), a membrane receptor involved in calcium ion influx and cell signal transduction (Behrendt et al, 2004;Bautista et al, 2007), is over-expressed in melanoma cells and some other types of cancer, such as prostate, breast and colorectal cancers (Zhang and Barritt, 2006;Johnson et al, 2009;Faridi et al, 2011), although in untransformed cells TRPM8 is mainly found in sensory neurons and some epithelial cells, and plays a role in cooling sensation (Bautista et al, 2007;Sabnis et al, 2008;Banner et al, 2011). Although there is a suggestion that TRPM8 is related to tumoriogenesis and cancer cell physiology (Zhang and Barritt, 2006;Prevarskaya et al, 2007a;2007b), there is only limited evidence to support this idea.…”