CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries.
The regulation of arterial tone is critical in the spatial and temporal control of cerebral blood flow. Voltage-gated Ca(2+) (CaV) channels are key regulators of excitation-contraction coupling in arterial smooth muscle, and thereby of arterial tone. Although L- and T-type CaV channels have been identified in rodent smooth muscle, little is known about the expression and function of specific CaV subtypes in human arteries. Here, we determined which CaV subtypes are present in human cerebral arteries and defined their roles in determining arterial tone. Quantitative polymerase chain reaction and Western blot analysis, respectively, identified mRNA and protein for L- and T-type channels in smooth muscle of cerebral arteries harvested from patients undergoing resection surgery. Analogous to rodents, CaV1.2 (L-type) and CaV3.2 (T-type) α1 subunits were expressed in human cerebral arterial smooth muscle; intriguingly, the CaV3.1 (T-type) subtype present in rodents was replaced with a different T-type isoform, CaV3.3, in humans. Using established pharmacological and electrophysiological tools, we separated and characterized the unique profiles of Ca(2+) channel subtypes. Pressurized vessel myography identified a key role for CaV1.2 and CaV3.3 channels in mediating cerebral arterial constriction, with the former and latter predominating at higher and lower intraluminal pressures, respectively. In contrast, CaV3.2 antagonized arterial tone through downstream regulation of the large-conductance Ca(2+)-activated K(+) channel. Computational analysis indicated that each Ca(2+) channel subtype will uniquely contribute to the dynamic regulation of cerebral blood flow. In conclusion, this study documents the expression of three distinct Ca(2+) channel subtypes in human cerebral arteries and further shows how they act together to orchestrate arterial tone.
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
Osama F
OF
Harraz
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Frank
F
Visser
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Suzanne E
SE
Brett
Department of Medical Biophysics, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Daniel
D
Goldman
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Anil
A
Zechariah
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Ahmed M
AM
Hashad
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Bijoy K
BK
Menon
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Tim
T
Watson
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
Yves
Y
Starreveld
Department of Physiology and Pharmacology, Hotchkiss Brain and Libin Cardiovascular Institutes, and Molecular Core Facility, Hotchkiss Brain Institute, and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta T2N 4N1, Canada dwelsh@ucalgary.ca.
Donald G
DG
Welsh
D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000378:metabolism* / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014661:Vasoconstriction
C479952:CACNA1H protein, human; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; C419385:L-type calcium channel alpha(1C); D020033:Protein Isoforms