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Diacylglycerol ‐induced suppression of vascular KCNQ channels ‐A common mechanism of action of vasoconstrictor hormones?
Author(s) -
Mani Bharath,
Brueggemann Lioubov,
Byron Kenneth
Publication year - 2009
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.23.1_supplement.579.1
Subject(s) - diacylglycerol kinase , activator (genetics) , protein kinase c , chemistry , vascular smooth muscle , trpc6 , medicine , endocrinology , phospholipase c , potassium channel , transient receptor potential channel , receptor , microbiology and biotechnology , biology , signal transduction , biochemistry , smooth muscle
Vasoconstrictor hormones increase cytosolic Ca 2+ concentration in vascular smooth muscle cells (SMC) by binding to receptors that activate phospholipase C, resulting in production of diacylglycerol (DAG). DAG is a known activator of protein kinase (PKC) and a direct activator of some non‐selective cation channels. In A7r5 rat aortic SMC, we had previously shown that Arg 8 ‐vasopressin (AVP), induces repetitive Ca 2+ transients (Ca 2+ spiking) by PKC‐dependent suppression of KCNQ potassium channels. We examined the role of DAG using fura‐2 Ca 2+ measurements and electrophysiological recordings in A7r5 cells. A DAG analogue, OAG (100µM), inhibited KCNQ currents by 56% at ‐20mV. OAG also activated a non‐selective cation current (I CAT ) and stimulated Ca 2+ spiking. Inhibition of PKC using 2µM Ro‐31‐8220 completely abolished OAG‐induced Ca 2+ spiking. TRPC6 knockdown (by expression of TRPC6 shRNA) abolished I CAT but only modestly delayed the onset of AVP‐ or OAG‐induced Ca 2+ spiking. These results suggest that while activation of TRPC6 channels contributes to AVP‐induced Ca 2+ spiking, DAG‐induced suppression of KCNQ channels is the primary mediator of the response. Another vasoconstrictor hormone serotonin (10nM) also inhibited 94% of KCNQ current and stimulated Ca 2+ spiking. Hence DAG‐mediated suppression of KCNQ channels might be a common mechanism by which vasoconstrictor hormones initiate Ca 2+ responses.