IP3 constricts cerebral arteries via IP3 receptor-mediated TRPC3 channel activation and independently of sarcoplasmic reticulum Ca2+ release

Qi Xi, Adebowale Adebiyi, Guiling Zhao, Kenneth E. Chapman, Christopher Waters, Aviv Hassid, Jonathan Jaggar

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Vasoconstrictors that bind to phospholipase C-coupled receptors elevate inositol-1,4,5-trisphosphate (IP3). IP3 is generally considered to elevate intracellular Ca concentration ([Ca]i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP3 receptors, leading to intracellular Ca release. We show that IP3 also stimulates vasoconstriction via a SR Ca release-independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca was depleted to abolish Ca release (measured using D1ER, a fluorescence resonance energy transfer-based SR Ca indicator), IP3 activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (ICat) caused by Na influx, induced membrane depolarization, elevated [Ca]i, and stimulated vasoconstriction. The IP3-induced ICat and [Ca]i elevation were attenuated by cation channel (Gd, 2-APB) and IP3 receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca channel blockers, reduced the SR Ca release-independent, IP3-induced [Ca]i elevation and vasoconstriction. In pressurized arteries, SR Ca depletion did not alter IP3-induced constriction at 20 mm Hg but reduced IP3-induced constriction by ≈39% at 60 mm Hg. [Ca]i elevations and constrictions induced by endothelin-1, a phospholipase C-coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca-depleted arteries. In summary, we describe a novel mechanism of IP3-induced vasoconstriction that does not occur as a result of SR Ca release but because of IP3 receptor-dependent ICat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca channels, leading to a myocyte [Ca]i elevation, and vasoconstriction.

Original languageEnglish (US)
Pages (from-to)1118-1126
Number of pages9
JournalCirculation research
Volume102
Issue number9
DOIs
StatePublished - May 1 2008

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Inositol 1,4,5-Trisphosphate Receptors
Cerebral Arteries
Sarcoplasmic Reticulum
Vasoconstriction
Constriction
Muscle Cells
Cations
Arteries
Type C Phospholipases
Transient Receptor Potential Channels
Nimodipine
Fluorescence Resonance Energy Transfer
Inositol 1,4,5-Trisphosphate
Membranes
TRPC3 cation channel
Diltiazem
Vasoconstrictor Agents
Endothelin-1
Inositol
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

IP3 constricts cerebral arteries via IP3 receptor-mediated TRPC3 channel activation and independently of sarcoplasmic reticulum Ca2+ release. / Xi, Qi; Adebiyi, Adebowale; Zhao, Guiling; Chapman, Kenneth E.; Waters, Christopher; Hassid, Aviv; Jaggar, Jonathan.

In: Circulation research, Vol. 102, No. 9, 01.05.2008, p. 1118-1126.

Research output: Contribution to journalArticle

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T1 - IP3 constricts cerebral arteries via IP3 receptor-mediated TRPC3 channel activation and independently of sarcoplasmic reticulum Ca2+ release

AU - Xi, Qi

AU - Adebiyi, Adebowale

AU - Zhao, Guiling

AU - Chapman, Kenneth E.

AU - Waters, Christopher

AU - Hassid, Aviv

AU - Jaggar, Jonathan

PY - 2008/5/1

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N2 - Vasoconstrictors that bind to phospholipase C-coupled receptors elevate inositol-1,4,5-trisphosphate (IP3). IP3 is generally considered to elevate intracellular Ca concentration ([Ca]i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP3 receptors, leading to intracellular Ca release. We show that IP3 also stimulates vasoconstriction via a SR Ca release-independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca was depleted to abolish Ca release (measured using D1ER, a fluorescence resonance energy transfer-based SR Ca indicator), IP3 activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (ICat) caused by Na influx, induced membrane depolarization, elevated [Ca]i, and stimulated vasoconstriction. The IP3-induced ICat and [Ca]i elevation were attenuated by cation channel (Gd, 2-APB) and IP3 receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca channel blockers, reduced the SR Ca release-independent, IP3-induced [Ca]i elevation and vasoconstriction. In pressurized arteries, SR Ca depletion did not alter IP3-induced constriction at 20 mm Hg but reduced IP3-induced constriction by ≈39% at 60 mm Hg. [Ca]i elevations and constrictions induced by endothelin-1, a phospholipase C-coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca-depleted arteries. In summary, we describe a novel mechanism of IP3-induced vasoconstriction that does not occur as a result of SR Ca release but because of IP3 receptor-dependent ICat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca channels, leading to a myocyte [Ca]i elevation, and vasoconstriction.

AB - Vasoconstrictors that bind to phospholipase C-coupled receptors elevate inositol-1,4,5-trisphosphate (IP3). IP3 is generally considered to elevate intracellular Ca concentration ([Ca]i) in arterial myocytes and induce vasoconstriction via a single mechanism: by activating sarcoplasmic reticulum (SR)-localized IP3 receptors, leading to intracellular Ca release. We show that IP3 also stimulates vasoconstriction via a SR Ca release-independent mechanism. In isolated cerebral artery myocytes and arteries in which SR Ca was depleted to abolish Ca release (measured using D1ER, a fluorescence resonance energy transfer-based SR Ca indicator), IP3 activated 15 pS sarcolemmal cation channels, generated a whole-cell cation current (ICat) caused by Na influx, induced membrane depolarization, elevated [Ca]i, and stimulated vasoconstriction. The IP3-induced ICat and [Ca]i elevation were attenuated by cation channel (Gd, 2-APB) and IP3 receptor (xestospongin C, heparin, 2-APB) blockers. TRPC3 (canonical transient receptor potential 3) channel knockdown with short hairpin RNA and diltiazem and nimodipine, voltage-dependent Ca channel blockers, reduced the SR Ca release-independent, IP3-induced [Ca]i elevation and vasoconstriction. In pressurized arteries, SR Ca depletion did not alter IP3-induced constriction at 20 mm Hg but reduced IP3-induced constriction by ≈39% at 60 mm Hg. [Ca]i elevations and constrictions induced by endothelin-1, a phospholipase C-coupled receptor agonist, were both attenuated by TRPC3 knockdown and xestospongin C in SR Ca-depleted arteries. In summary, we describe a novel mechanism of IP3-induced vasoconstriction that does not occur as a result of SR Ca release but because of IP3 receptor-dependent ICat activation that requires TRPC3 channels. The resulting membrane depolarization activates voltage-dependent Ca channels, leading to a myocyte [Ca]i elevation, and vasoconstriction.

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