Abnormal Coronary Function in Mice Deficient in α _1H T-type Ca ²⁺ Channels

Abstract

Calcium ion (Ca2+) influx through voltage-gated Ca2+ channels is important for the regulation of vascular tone. Activation of L-type Ca2+ channels initiates muscle contraction; however, the role of T-type Ca2+ channels (T-channels) is not clear. We show that mice deficient in the alpha1H T-type Ca2+ channel (alpha(1)3.2-null) have constitutively constricted coronary arterioles and focal myocardial fibrosis. Coronary arteries isolated from alpha(1)3.2-null arteries showed normal contractile responses, but reduced relaxation in response to acetylcholine and nitroprusside. Furthermore, acute blockade of T-channels with Ni2+ prevented relaxation of wild-type coronary arteries. Thus, Ca2+ influx through alpha1H T-type Ca2+ channels is essential for normal relaxation of coronary arteries.

Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort

“…28 However, Cacna1h-deficient mice have no reported ptosis but rather cardiac fibrosis, which our two patients with CACNA1H homozygous truncation do not have. 29 Interestingly, heterozygous missense changes in CACNA1H have been associated with childhood epilepsy, but the two sisters we describe with a homozygous truncating mutation in this gene are completely normal neurologically except for ptosis. 30 This may suggest a different disease mechanism than we have previously shown for other genes in which biallelic loss of function results in distinct clinical phenotypes as compared with heterozygous mutations.…”

Flagellar ion channels of sperm: similarities and differences between species

“…Specific ion channels mediate the rise in [Ca 2+ ] i within sperm, and many candidates for the principle Ca 2+ channel in sperm, including various voltagegated Ca 2+ channels, were proposed based primarily on studies using Ca 2+ imaging, immunolabeling, and patch-clamp experiments from sperm precursors [61][62][63]. However, genetic ablation studies suggested that these candidate proteins were not functionally necessary for male fertility or some compensatory mechanism for their loss may be present [64][65][66][67][68]. The molecular identity of the first sperm specific ion channel required for male fertility in mice was determined in 2001 with the cloning of CatSper1 [24].…”

The genetic background affects the vascular response in T‐type calcium channels 3.2 deficient mice

“…The Ca v 3.1-deficient mice have a blunted hypertensive response to infusion of L-NAME, which suggest that vascular-expressed Ca v 3.1 is important for bioavailability of NO and peripheral resistance (Svenningsen et al 2014). Ca v 3.2-deficient mice have abnormal coronary function with normal vasoconstrictor responses but reduced relaxation of coronary vascular smooth muscle after acetylcholine and nitroprusside (Chen et al 2003).…”

“…cells; however, T-type calcium channels are also expressed in the cardiovascular system where they play a functional role in the regulation of both contraction and vasodilation (Hansen et al 2001, Chen et al 2003. The family of T-type channels is comprised of three isoforms: Ca v 3.1, Ca v 3.2 and Ca v 3.3, which have all been identified in the vasculature (Gustafsson et al 2001, Hansen et al 2001.…”

“…Our data from the mice on mixed background are consistent with the recently published findings from rat cerebral arteries (Harraz et al 2014) and suggest that Ca v 3.2 in vascular smooth muscle cell of mice on the mixed background is important for the activation of a pathway leading to dilatation. It is proposed that Ca v 3.2 is functionally coupled to the large calcium-activated potassium channel (BK Ca ) (Chen et al 2003) and that the activation of Cav3.2 induces vasodilation through a BK Camediated hyperpolarization (Harraz et al 2014). Although mesenteric arteries from C57BL/6 WT and Ca v 3.2 À/À mice express BKca, the ablation of Ca v 3.2 did not affect the depolarization-induced constriction and subsequent dilatation, suggesting that the functional coupling between the two channels is not the rate-limiting step in C57BL/6 mice.…”