Researchers have performed the first human-based study to identify calcium channels in cerebral arteries and determine the distinct role each channel plays in helping control blood flow to the brain. The study appears in the May issue of the Journal of General Physiology.
The contractile activity of smooth muscle cells in the walls of cerebral arteries determines the degree of constriction they experience (known as arterial tone) and thereby controls blood flow. Arterial tone is regulated in large part by the influx of calcium through voltage-gated calcium (CaV) channels, which are found in the membranes of excitable cells throughout the body. However, much of what is known about the identity and function of brain arterial CaV channels comes from experiments in rodents.
To uncover the identities and roles of these channels in humans, Donald Welsh and colleagues from the University of Calgary investigated smooth muscle cells from cerebral arteries harvested from patients undergoing brain surgery. As in rodents, the researchers found one L-type (“long-lasting”) channel (CaV1.2) and two T-type (“transient”) channels (CaV3.2, and 3.3) in the human smooth muscle cells.
Welsh and colleagues found that, although CaV1.2 and CaV3.3 are different channel types, they both mediate constriction so that blocking them dilates the arteries and increases blood flow, with CaV1.2 playing a bigger role at higher pressures and CaV3.3 at lower pressures. Using a computational model to analyze the effects of blocking these channels, they determined that blocking CaV1.2 would have a particularly dramatic effect on blood flow in larger arteries, which have higher pressure. In marked contrast, the model shows that CaV3.3 has the opposite effect on blood flow. This channel promotes vasodilation so that blocking it constricts arteries and decreases the flow of blood.
The findings reveal that each of the channel subtypes in human cerebral arteries play a different role in the regulation of arterial tone. Moreover, this is the first study that implicates T-type channels in the regulation of blood flow in human cerebral arteries. Understanding all of these distinctions will be important to the development of drugs that manipulate specific channels to either suppress or enhance regional blood flow.
About this neuroscience research
Funding: The study received funding from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada.
Source: Rita Sullivan King – Rockefeller University Press Image Credit: The image is credited to Harraz et al., 2015 Original Research:Abstract for “CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries” by Osama F. Harraz, Frank Visser, Suzanne E. Brett, Daniel Goldman, Anil Zechariah, Ahmed M. Hashad, Bijoy K. Menon, Tim Watson, Yves Starreveld, and Donald G. Welsh in Journal of General Physiology. Published online April 27 2015 doi:10.1085/jgp.201511361
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 Ca2+ (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 Ca2+ 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 Ca2+-activated K+ channel. Computational analysis indicated that each Ca2+ channel subtype will uniquely contribute to the dynamic regulation of cerebral blood flow. In conclusion, this study documents the expression of three distinct Ca2+ channel subtypes in human cerebral arteries and further shows how they act together to orchestrate arterial tone.
“CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries” by Osama F. Harraz, Frank Visser, Suzanne E. Brett, Daniel Goldman, Anil Zechariah, Ahmed M. Hashad, Bijoy K. Menon, Tim Watson, Yves Starreveld, and Donald G. Welsh in Journal of General Physiology. Published online April 27 2015 doi:10.1085/jgp.201511361