TREK-1 regulation by nitric oxide and cGMP-dependent protein kinase - An essential role in smooth muscle inhibitory neurotransmission

Potassium channels activated by membrane stretch may contribute to maintena nce of relaxation of smooth muscle cells in visceral hollow organs. Previou s work has identified K+ channels in murine colon that are activated by str etch and further regulated by NO-dependent mechanisms. We have screened mur ine gastrointestinal, vascular, bladder, and uterine smooth muscles for the expression of TREK and TRAAK mRNA. Although TREK-1 was expressed in many o f these smooth muscles, TREK-2 was expressed only in murine antrum and pulm onary artery. TRAAK was not expressed in any smooth muscle cells tested. Wh ole cell currents from TREK-1 expressed in mammalian COS cells were activat ed by stretch, and single channel re cordings showed that the stretch-depen dent conductance was due to 90 pS channels. Sodium nitroprusside (10(-6) or 10(-5) M) and 8-Br-cGMP (10(-4) or 10(-3) M) increased TREK-1 currents in perforated whole cell and single channel recordings. Mutation of the PKG co nsensus sequence at serine 351 blocked the stimulatory effects of sodium ni troprusside and 8-Br-cGMP on open probability without affecting the inhibit ory effects of 8-Br-cAMP. TREK-1 encodes a component of the stretch-activat ed K+ conductance in smooth muscles and may contribute to nitrergic inhibit ion of gastrointestinal muscles.