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IP3 constricts cerebral arteries by activating a non‐selective cation current in myocytes
Author(s) -
Xi Qi,
Jaggar Jonathan H
Publication year - 2007
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.21.6.a1350
Subject(s) - myocyte , chemistry , depolarization , patch clamp , thapsigargin , biophysics , second messenger system , inositol , channel blocker , extracellular , medicine , calcium , intracellular , biochemistry , receptor , biology , organic chemistry
Inositol 1,4,5‐trisphosphate (IP 3 ) is a principal second messenger that promotes changes in intracellular calcium (Ca 2+ ) signals, but mechanisms mediating these effects in arterial myocytes are unclear. Here, we investigated IP 3 regulation of Ca 2+ signaling in cerebral artery myocytes. Bt‐IP 3 (10 μM), a membrane permeant IP 3 analog, caused a sustained increase in [Ca 2+ ] i that was partially blocked by Gd 3+ , a non‐selective cation current (I Cat ) blocker, 2‐APB, a I Cat and IP 3 receptor blocker, and diltiazem, a voltage‐operated Ca 2+ channel blocker. Surprisingly, in cells pretreated with thapsigargin (100 nM), or thaspigargin (1 μM) + caffeine (10 mM), to deplete SR Ca 2+ load, Bt‐IP 3 (10 μM) also caused a sustained [Ca 2+ ] i elevation that was blocked by removal of extracellular Ca 2+ . When using patch‐clamp electrophysiology in cells in which SR Ca 2+ load was depleted, we found that IP 3 , Bt‐IP 3 , or flash photolysis of caged‐IP 3 , activated a Gd 3+ ‐sensitive I Cat that was profoundly attenuated by a reduction in extracellular [Na + ]. In myocytes with depleted SR Ca 2+ , Bt‐IP 3 also activated single channels that were not observed in control. In SR Ca 2+ depleted pressurized arteries, Bt‐IP 3 induced a 15 mV depolarization and a vasoconstriction that was reversed by 2‐APB. In contrast to Bt‐IP 3 , L‐Bt‐IP 3 (10 μM), an inactive IP 3 analog, did not elevate [Ca 2+ ] i in myocytes or alter pressurized artery diameter. In summary, data suggest that IP 3 activates a I Cat in cerebral artery myocytes independent of SR Ca 2+ release, leading to membrane depolarization, voltage‐dependent Ca 2+ channel activation, an [Ca 2+ ] i elevation and constriction. NIH/AHA