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Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.

ABSTRACT: Although it is well established that changes in endothelial intracellular [Ca(2+)] regulate endothelium-dependent vasodilatory pathways, the molecular identities of the ion channels responsible for Ca(2+) influx in these cells are not clearly defined. The sole member of the ankyrin (A) transient receptor potential (TRP) subfamily, TRPA1, is a Ca(2+)-permeable nonselective cation channel activated by electrophilic compounds such as acrolein (tear gas), allicin (garlic), and allyl isothiocyanate (AITC) (mustard oil). The present study examines the hypothesis that Ca(2+) influx via TRPA1 causes endothelium-dependent vasodilation. The effects of TRPA1 activity on vascular tone were examined using isolated, pressurized cerebral arteries. AITC induced concentration-dependent dilation of pressurized vessels with myogenic tone that was accompanied by a corresponding decrease in smooth muscle intracellular [Ca(2+)]. AITC-induced dilation was attenuated by disruption of the endothelium and when the TRPA1 channel blocker HC-030031 was present in the arterial lumen. TRPA1 channels were found to be present in native endothelial cells, localized to endothelial cell membrane projections proximal to vascular smooth muscle cells. AITC-induced dilation was insensitive to nitric oxide synthase or cyclooxygenase inhibition but was blocked by luminal administration of the small and intermediate conductance Ca(2+)-activated K(+) channel blockers apamin and TRAM34. BaCl(2), a blocker of inwardly rectifying K(+) channels, also inhibited AITC-induced dilation. AITC-induced smooth muscle cell hyperpolarization was blocked by apamin and TRAM34. We conclude that Ca(2+) influx via endothelial TRPA1 channels elicits vasodilation of cerebral arteries by a mechanism involving endothelial cell Ca(2+)-activated K(+) channels and inwardly rectifying K(+) channels in arterial myocytes.

SUBMITTER: Earley S

PROVIDER: S-EPMC2966339 | biostudies-other | 2009 Apr

REPOSITORIES: biostudies-other

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Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.

Earley Scott S Gonzales Albert L AL Crnich Rachael R

Circulation research 20090319 8

Although it is well established that changes in endothelial intracellular [Ca(2+)] regulate endothelium-dependent vasodilatory pathways, the molecular identities of the ion channels responsible for Ca(2+) influx in these cells are not clearly defined. The sole member of the ankyrin (A) transient receptor potential (TRP) subfamily, TRPA1, is a Ca(2+)-permeable nonselective cation channel activated by electrophilic compounds such as acrolein (tear gas), allicin (garlic), and allyl isothiocyanate ( ...[more]

PMID: 19299646

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Project description:Merkel cell-neurite complexes are highly sensitive touch receptors comprising epidermal Merkel cells and sensory afferents. Based on morphological and molecular studies, Merkel cells are proposed to be mechanosensory cells that signal afferents via neurotransmission; however, functional studies testing this hypothesis in intact skin have produced conflicting results. To test this model in a simplified system, we asked whether purified Merkel cells are directly activated by mechanical stimulation. Cell shape was manipulated with anisotonic solution changes and responses were monitored by Ca2+ imaging with fura-2. We found that hypotonic-induced cell swelling, but not hypertonic solutions, triggered cytoplasmic Ca2+ transients. Several lines of evidence indicate that these signals arise from swelling-activated Ca2+-permeable ion channels. First, transients were reversibly abolished by chelating extracellular Ca2+, demonstrating a requirement for Ca2+ influx across the plasma membrane. Second, Ca2+ transients were initially observed near the plasma membrane in cytoplasmic processes. Third, voltage-activated Ca2+ channel (VACC) antagonists reduced transients by half, suggesting that swelling-activated channels depolarize plasma membranes to activate VACCs. Finally, emptying internal Ca2+ stores attenuated transients by 80%, suggesting Ca2+ release from stores augments swelling-activated Ca2+ signals. To identify candidate mechanotransduction channels, we used RT-PCR to amplify ion-channel transcripts whose pharmacological profiles matched those of hypotonic-evoked Ca2+ signals in Merkel cells. We found 11 amplicons, including PKD1, PKD2, and TRPC1, channels previously implicated in mechanotransduction in other cells. Collectively, these results directly demonstrate that Merkel cells are activated by hypotonic-evoked swelling, identify cellular signaling mechanisms that mediate these responses, and support the hypothesis that Merkel cells contribute to touch reception in the Merkel cell-neurite complex.

Dataset Information

Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.

Publications

Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels.

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