Calcium ion (Ca ²⁺ ) influx through voltage-gated Ca ²⁺ channels is important for the regulation of vascular tone. Activation of L-type Ca ²⁺ channels initiates muscle contraction; however, the role of T-type Ca ²⁺ channels (T-channels) is not clear. We show that mice deficient in the α _1H T-type Ca ²⁺ channel (α ₁ 3.2-null) have constitutively constricted coronary arterioles and focal myocardial fibrosis. Coronary arteries isolated from α 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 Ni ²⁺ prevented relaxation of wild-type coronary arteries. Thus, Ca ²⁺ influx through α _1H T-type Ca ²⁺ channels is essential for normal relaxation of coronary arteries.

In both humans and animals, an insult to the brain can lead, after a variable latent period, to the appearance of spontaneous epileptic seizures that persist for life. The underlying processes, collectively referred to as epileptogenesis, include multiple structural and functional neuronal alterations. We have identified the T-type Ca²⁺channel Ca_v3.2 as a central player in epileptogenesis. We show that a transient and selective upregulation of Ca_v3.2 subunits on the mRNA and protein levels after status epilepticus causes an increase in cellular T-type Ca²⁺currents and a transitional increase in intrinsic burst firing. These functional changes are absent in mice lacking Ca_v3.2 subunits. Intriguingly, the development of neuropathological hallmarks of chronic epilepsy, such as subfield-specific neuron loss in the hippocampal formation and mossy fiber sprouting, was virtually completely absent in Ca_v3.2^−/−mice. In addition, the appearance of spontaneous seizures was dramatically reduced in these mice. Together, these data establish transcriptional induction of Ca_v3.2 as a critical step in epileptogenesis and neuronal vulnerability.

Voltage-gated T-type Ca ²⁺ channels (T-channels) are normally expressed during embryonic development in ventricular myocytes but are undetectable in adult ventricular myocytes. Interestingly, T-channels are reexpressed in hypertrophied or failing hearts. It is unclear whether T-channels play a role in the pathogenesis of cardiomyopathy and what the mechanism might be. Here we show that the α _1H voltage-gated T-type Ca ²⁺ channel (Ca _v 3.2) is involved in the pathogenesis of cardiac hypertrophy via the activation of calcineurin/nuclear factor of activated T cells (NFAT) pathway. Specifically, pressure overload–induced hypertrophy was severely suppressed in mice deficient for Ca _v 3.2 (Ca _v 3.2 ^−/− ) but not in mice deficient for Ca _v 3.1 (Ca _v 3.1 ^−/− ). Angiotensin II–induced cardiac hypertrophy was also suppressed in Ca _v 3.2 ^−/− mice. Consistent with these findings, cultured neonatal myocytes isolated from Ca _v 3.2 ^−/− mice fail to respond hypertrophic stimulation by treatment with angiotensin II. Together, these results demonstrate the importance of Ca _v 3.2 in the development of cardiac hypertrophy both in vitro and in vivo. To test whether Ca _v 3.2 mediates the hypertrophic response through the calcineurin/NFAT pathway, we generated Ca _v 3.2 ^−/− , NFAT-luciferase reporter mice and showed that NFAT-luciferase reporter activity failed to increase after pressure overload in the Ca _v 3.2 ^−/− /NFAT-Luc mice. Our results provide strong genetic evidence that Ca _v 3.2 indeed plays a pivotal role in the induction of calcineurin/NFAT hypertrophic signaling and is crucial for the activation of pathological cardiac hypertrophy.

A novel gene (Cacng2;γ₂ ) encoding a protein similar to the voltage-activated Ca²⁺ channel γ₁ subunit was identified as the defective gene in the epileptic and ataxic mouse, stargazer. In this study, we analyzed the association of this novel neuronal γ₂ subunit with Ca²⁺ channels of rabbit brain, and the function of the γ₂ subunit in recombinant neuronal Ca²⁺ channels expressed inXenopus oocytes. Our results showed that the γ₂ subunit and a closely related protein (called γ₃) co-sedimented and co-immunoprecipitated with neuronal Ca²⁺ channel subunits in vivo. Electrophysiological analyses showed that γ₂co-expression caused a significant decrease in the current amplitude of both α_1B(α₁2.2)-class (36.8%) and α_1A(α₁2.1)-class (39.7%) Ca²⁺channels (α₁β₃α₂δ). Interestingly, the inhibitory effects of the γ₂ subunit on current amplitude were dependent on the co-expression of the α₂δ subunit. In addition, co-expression of γ₂ or γ₁ also significantly decelerates the activation kinetics of α_1B-class Ca²⁺channels. Taken together, these results suggest that the γ₂ subunit is an important constituent of the neuronal Ca²⁺ channel complex and that it down-regulates neuronal Ca²⁺ channel activity. Furthermore, the γ₂ subunit likely contributes to the fine-tuning of neuronal Ca²⁺ channels by counterbalancing the effects of the α₂δ subunit.