CaV1.2/CaV3.x channels mediate divergent vasomotor responses in human cerebral arteries

Abstract

Human cerebral arteries contain three Ca2+ channel subtypes with distinct physiological roles.

Genetic Ablation of Ca V 3.2 Channels Enhances the Arterial Myogenic Response by Modulating the RyR-BK Ca Axis

“…This negative feedback response entails a modulatory paradigm in which Ca 2+ flux through Ca V 3.2 channel triggers Ca 2+ spark generation and then activates BK Ca channels to hyperpolarize and relax arteries (Figure III in the online-only Data Supplement). This novel functional axis, recently described in the human cerebral circulation, 31 challenges the traditional view that voltage-gated Ca 2+ channels solely facilitate arterial tone development.…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…This highlights the function of T-type calcium channels as regulators of pacemaking in the heart (Mesirca et al, 2014(Mesirca et al, , 2015. A recent study revealed that Ca V 3.2 T-type calcium channels are also critically important for relaxation of cerebral arteries by contributing to a negative feedback loop that involves calcium-induced calcium release from RyRs and subsequent activation of calcium-dependent potassium conductances (Harraz et al, 2014(Harraz et al, , 2015. This then would suggest that T-type calcium channel blockers could act in some cases as vasoconstrictors.…”

“…By contrast, Ca V 3.3 in human cerebral arteries contributes to smooth muscle cell contraction in cooperation with Ca V 1.2. (Harraz et al, 2015) T-type calcium channel activity has also been linked to gene transcription. Activation of T-type channels has been shown to activate nuclear factor of activated T cells in cartilage tissue (Lin et al, 2014) and during the development of cardiac hypertrophy (Hsu et al, 2013;Huang et al, 2013a).…”

T-type Ca2+channels and autoregulation of local blood flow

“…50 Human cerebral arteries express the Ca V 3.2 and Ca V 3.3 isoforms, and interestingly Ni 2C (50 mM) also increased myogenic tone in human arteries. 53 Moreover, the T-type blocker NNC 55-0396 (1 mM) inhibited the myogenic tone at lower pressures in human cerebral arteries in the presence of the L-type blocker nifedipine (200 nM), an effect that is reminiscent of the Ca V 3.1-mediated effects on myogenic tone in rodent arteries 46,78 but might be mediated via Ca V 3.3 channels in human cerebral arteries 53 …”

“…48,49,51,52 Interestingly, in human cerebral arteries the T-type isoforms expressed are the Ca V 3.2 and Ca V 3.3 channels, with no expression of Ca V 3.1 channels. 53 Application of 15 mmHg extracellular pressure to SW620 human cancer cells causes mechanical activation of Ca 2C influx through Ca V 3.3 T-type channels (but not through Ca V 3.1 or Ca V 3.2 channels), which activates PKC-b and stimulates proliferation of cancer cells. 54 There are no reports of direct mechano-sensitivity of Ca V 3.1 channels.…”