Pathophysiological Significance of T-type Ca2+ Channels: Expression of T-type Ca2+ Channels in Fetal and Diseased Heart

Abstract

Abstract. Re-expression of fetal genes has been considered to underlie ionic remodeling in diseased heart. T-type Ca 2+ channels have been reported to be functionally expressed in embryonic hearts. In this review, we summarize developmental changes of T-type Ca 2+ channels in mouse ventricles from 9.5 days postcoitum (dpc) to adulthood, using patch clamp and quantitative PCR. In addition, we introduced T-type Ca 2+ channel expression in hypertrophied ventricles caused by myocardial infarction (MI) and aortic banding (AOB). Substantial T-type Ca 2+ channel current was recorded at both 9.5 and 18 dpc. The currents were inhibited by Ni 2+ at low concentrations. The current was not detectable in the adult stage. Ca v 3.2 (α 1H ) mRNA is expressed dominantly at both 9.5 and 18 dpc. Ca v 3.1 (α 1G ) increases from 9.5 to 18 dpc, but remains at low level compared with Ca v 3.2. In contrast, Ca v 3.1 is greater than Ca v 3.2 at the adult stage. In MI, Ca v 3.1 mRNA correlates negatively with brain natriuretic peptide (BNP) mRNA, whereas Ca v 3.2 mRNA correlates positively with BNP mRNA. In AOB, these correlations are weak. We also analyzed the neuron-restrictive silencer factor (NRSF) in these hearts because it is the suppressor of transcription of the fetal cardiac gene program. The negative correlation between NRSF and BNP was stronger in MI than in AOB. Our findings show that Ca v 3.2 underlies the functional T-type Ca 2+ channel in embryonic heart and suggest that NRSF may regulate Ca v 3.2 expression in diseased hearts.

Transcriptional Regulation of the Fetal Cardiac Gene Program

“…In addition, the HCN4 gene is positively regulated by AP-1 and MEF-2 proteins, whose binding sequences are both located within the gene's first intron (37). expression is suppressed in the adult ventricle such that they are restricted to the conduction system (38,39). However, T-type Ca 2+ channels are re-expressed in hypertrophied and failing ventricles, and the resultant Ttype Ca 2+ currents (I ca,T ) are thought to be involved in pathological processes leading to systolic dysfunction and arrhythmogenesis (40).…”

Maintenance Of Calcium Homeostasis in Embryonic Stem Cell-Derived Cardiomyocytes

“…Ca V 3.1 mRNA and protein were simultaneously detected as early as embryonic day 14 (E14) after the heart has fully matured in vivo within mouse embryos (Cribbs et al, 2001). In a separate experiment, the mRNA level of Ca V 3.1 was moderately reduced from E18 when compared to its expression at adult stage (Yasui et al, 2005). Ni 2+ at a high concentration of 100μM could be used to selectively block 50% of Ca V 3.1 T-type channels.…”

“…Ca V 3.2 mRNA was detected as early as eight-week gestation in humans (Qu and Boutjdir, 2001). In mouse, the expression of Ca V 3.2 was also measured at three time-points; its mRNA was detected as early as E9.5 and then its level was decreased by E18 until it was no longer detected at adult stage (Yasui et al, 2005). Again, Ca V 3.2 has been studied in vitro.…”

Pathophysiological Significance of T-type Ca2+ Channels: T-type Ca2+ Channels and Drug Development

“…In the heart, T-type Ca 2+ channels are expressed in the sinoatrial node and are considered to participate in cardiac pacemaking (4,5), but not in normal myocardial contraction, as described below. The expression of T-type Ca 2+ channels was shown to be increased in immature hearts (6) and proposed to be involved in the development of pathological conditions such as ventricular hypertrophy (6 -8), myocardial infarction (9), cardiomyopathy (10,11), heart failure (12), and atrial fibrilation (13,14). T-type Ca 2+ channels are expressed in various arteries and veins with a distribution different from that of L-type Ca 2+ channels and are considered to participate in regulation of microcirculation (15 -18).…”