Bidirectional TRP/L Type Ca(2+) Channel/RyR/BK(Ca) Molecular and Functional Signaloplex in Vascular Smooth Muscles

TRP channels are expressed both in vascular myocytes and endothelial cells, but knowledge of their operational mechanisms in vascular tissue is particularly limited. Here, we show for the first time the biphasic contractile reaction with relaxation followed by a contraction in response to TRPV4 agonist, GSK1016790A, in a rat pulmonary artery preconstricted with phenylephrine. Similar responses were observed both with and without endothelium, and these were abolished by the TRPV4 selective blocker, HC067047, confirming the specific role of TRPV4 in vascular myocytes. Using selective blockers of BK(Ca) and L-type voltage-gated Ca(2+) channels (Ca(L)), we found that the relaxation phase was inducted by BK(Ca) activation generating STOCs, while subsequent slowly developing TRPV4-mediated depolarisation activated Ca(L), producing the second contraction phase. These results are compared to TRPM8 activation using menthol in rat tail artery. Activation of both types of TRP channels produces highly similar changes in membrane potential, namely slow depolarisation with concurrent brief hyperpolarisations due to STOCs. We thus propose a general concept of bidirectional TRP-Ca(L)-RyR-BK(Ca) molecular and functional signaloplex in vascular smooth muscles. Accordingly, both TRPV4 and TRPM8 channels enhance local Ca(2+) signals producing STOCs via TRP–RyR–BK(Ca) coupling while simultaneously globally engaging BK(Ca) and Ca(L) channels by altering membrane potential.