We describe here several novel properties of the human ␣ 1G subunit that forms T-type calcium channels. The partial intron/exon structure of the corresponding gene CACNA1G was defined and several ␣ 1G isoforms were identified, especially two isoforms that exhibit a distinct III-IV loop: ␣ 1G-a and ␣ 1G-b . Northern blot and dot blot analyses indicated that ␣ 1G mRNA is predominantly expressed in the brain, especially in thalamus, cerebellum, and substantia nigra. Additional experiments have also provided evidence that ␣ 1G mRNA is expressed at a higher level during fetal life in nonneuronal tissues (i.e. kidney, heart, and lung). Functional expression in HEK 293 cells of a full-length cDNA encoding the shortest ␣ 1G isoform identified to date, ␣ 1G-b , resulted in transient, low threshold activated Ca 2؉ currents with the expected permeability ratio (I Sr > I Ca > I Ba ) and channel conductance (ϳ7 pS). These properties, together with slowly deactivating tail currents, are typical of those of native T-type Ca 2؉ channels. This ␣ 1G -related current was inhibited by mibefradil (IC 50 ‫؍‬ 2 M) and weakly blocked by Ni 2؉ ions (IC 50 ‫؍‬ 148 M) and amiloride (IC 50 > 1 mM). We showed that steady state activation and inactivation properties of this current can generate a "window current" in the range of ؊65 to ؊55 mV. Using neuronal action potential waveforms, we show that ␣ 1G channels produce a massive and sustained Ca 2؉ influx due to their slow deactivation properties. These latter properties would account for the specificity of Ca 2؉ influx via T-type channels that occurs in the range of physiological resting membrane potentials, differing considerably from the behavior of other Ca 2؉ channels.

The generation of the mammalian heartbeat is a complex and vital function requiring multiple and coordinated ionic channel activities. The functional role of low-voltage activated (LVA) T-type calcium channels in the pacemaker activity of the sinoatrial node (SAN) is, to date, unresolved. Here we show that disruption of the gene coding for CaV3.1/alpha1G T-type calcium channels (cacna1g) abolishes T-type calcium current (I(Ca,T)) in isolated cells from the SAN and the atrioventricular node without affecting the L-type Ca2+ current (I(Ca,L)). By using telemetric electrocardiograms on unrestrained mice and intracardiac recordings, we find that cacna1g inactivation causes bradycardia and delays atrioventricular conduction without affecting the excitability of the right atrium. Consistently, no I(Ca,T) was detected in right atrium myocytes in both wild-type and CaV3.1(-/-) mice. Furthermore, inactivation of cacna1g significantly slowed the intrinsic in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization. Our results demonstrate that CaV3.1/T-type Ca2+ channels contribute to SAN pacemaker activity and atrioventricular conduction.