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Nitric Oxide Inhibits IP 3 R‐mediated Activation of TRPM4 in Cerebral Artery Smooth Muscle Cells
Author(s) -
Gonzales Albert Louis,
Earley Scott
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.876.2
Subject(s) - chemistry , cyclic guanosine monophosphate , soluble guanylyl cyclase , nitric oxide , patch clamp , transient receptor potential channel , cgmp dependent protein kinase , myocyte , biophysics , receptor , protein kinase a , endocrinology , pharmacology , microbiology and biotechnology , biochemistry , kinase , biology , guanylate cyclase , organic chemistry , cyclin dependent kinase 2
The melastatin transient receptor potential channel TRPM4 is essential for pressure‐induced smooth muscle cell contraction and is activated by Ca 2+ released from the SR via inositol trisphosphate receptors (IP 3 R). 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 IP 3 R‐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 IP 3 analog, Bt‐IP 3 . 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 IP 3 R‐mediated activation of TRPM4. RO1HL091905; F31HL094145–01 (AG)