Nitric Oxide Inhibits IP3R‐mediated Activation of TRPM4 in Cerebral Artery Smooth Muscle Cells

Abstract

The melastatin transient receptor potential channel TRPM4 is essential for pressure‐induced smooth muscle cell contraction and is activated by Ca2+ released from the SR via inositol trisphosphate receptors (IP3R). Endothelium‐derived nitric oxide (NO) activates soluble guanylyl cyclase (sGC) leading to the generation of cyclic guanosine monophosphate (cGMP), activation of protein kinase G (PKG), and smooth muscle relaxation. We hypothesized that NO blocks IP3R‐dependent activation of TRPM4 channels in cerebral artery myocytes. Using perforated whole‐cell patch clamp electrophysiology, we observe a dose‐dependent reduction in TRPM4 channel activity in response to the NO donor S‐Nitroso‐N‐Acetyl‐D,L‐Penicillamine (SNAP). TRPM4 channel activity is also diminished following exposure to the cell‐permeable cGMP analog dibutyryl‐cGMP. TRPM4 currents inhibited by NO or cGMP did not return following administration of the cell‐permeable IP3 analog, Bt‐IP3. In addition, the sGC inhibitor NS‐2028 prevented NO‐mediated inhibition of TRPM4 channel activity. These findings suggest that NO can relax cerebral artery myocytes by blocking IP3R‐mediated activation of TRPM4. RO1HL091905; F31HL094145–01 (AG)