Vascular calcium channels and high blood pressure: Pathophysiology and therapeutic implications

Abstract

Long-lasting Ca 2+ (Ca L ) channels of the Ca v 1.2 gene family are heteromultimeric structures that are minimally composed of a pore-forming α 1C subunit and regulatory β and α 2 δ subunits in vascular smooth muscle cells. The Ca L channels are the primary pathways for voltage-gated Ca 2+ influx that trigger excitation-contraction coupling in small resistance vessels. Notably, vascular smooth muscle cells of hypertensive rats show an increased expression of Ca L channel α 1C subunits, which is associated with elevated Ca 2+ influx and the development of abnormal arterial tone. Indeed, blood pressure per se appears to promote Ca L channel expression in small arteries, and even short-term rises in pressure may alter channel expression. Membrane depolarization has been shown to be one stimulus associated with elevated blood pressure that promotes Ca L channel expression at the plasma membrane. Future studies to define the molecular processes that regulate Ca L channel expression in vascular smooth muscle cells will provide a rational basis for designing antihypertensive therapies to normalize Ca L channel expression and the development of anomalous vascular tone in hypertensive pathologies.

Molecular Basis for Zinc Transporter 1 Action as an Endogenous Inhibitor of L-type Calcium Channels

“…5 Conversely, our current data indicate, for the first time, that ZnT-1-induced inhibition of the LTCC involves an interaction between ZnT-1 and the ␤-subunit. This interaction was demonstrated both by co-immunoprecipitation of the two proteins and by measurement of a FRET signal between ZnT-1:Venus and ␤:Cerulean co-expressed in HEK293T cells, irrespective of the ␣ 1 -subunit.…”

“…Attempts to demonstrate an interaction between ZnT-1 and the LTCC ␣ 1 -subunit were unsuccessful (30). 5 Based on these results, we hypothesize that ZnT-1 indirectly antagonizes targeting of the ␣ 1 -subunit to the plasma membrane. Because the regulatory ␤-subunit is involved in trafficking of the LTCC to the plasma membrane (26,27), our present study aimed to determine whether a functional interaction of ZnT-1 with the ␤-subunit underlies its inhibitory effect.…”

“…tion of cardiac excitability (1), excitation-contraction coupling (2)(3)(4)(5), and synaptic vesicle release (6,7). They also modulate Ca 2ϩ homeostasis, hormone secretion, phosphorylation processes, and gene regulation (8).…”

Functional Importance of L- and P/Q-Type Voltage-Gated Calcium Channels in Human Renal Vasculature

“…Hypertensive rats have increased expression of L-type channels in vascular smooth muscle cells, and increased blood pressure and membrane depolarization promote channel expression at the cell membrane. 20 Whether this is true for humans need to be investigated.…”

Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension

“…There is evidence to suggest that high BP can modulate activation of calcium channels via changes in their expression level or by affecting their functional ionic conductance (Stekiel et al, 1986;Pesic et al, 2004). Such effects can exacerbate vasoconstriction and elevate vascular resistance and BP; hence, treatment strategies to reduce high BP have long involved the use of Ltype VGCC inhibitors (Sonkusare et al, 2006). Further, Ca 2+ channel blockers which dilate resistance arteries have been shown to reverse eutrophic remodelling (Schiffrin, 2004;Agabiti-Rosei & Rizzoni, 2010).…”