Differential Distribution of Three Members of a Gene Family Encoding Low Voltage-Activated (T-Type) Calcium Channels

Abstract

Low voltage-activated (T-type) calcium currents are observed in many central and peripheral neurons and display distinct physiological and functional properties. Using in situ hybridization, we have localized central and peripheral nervous system expression of three transcripts (alpha1G, alpha1H, and alpha1I) of the T-type calcium channel family (CaVT). Each mRNA demonstrated a unique distribution, and expression of the three genes was largely complementary. We found high levels of expression of these transcripts in regions associated with prominent T-type currents, including inferior olivary and thalamic relay neurons (which expressed alpha1G), sensory ganglia, pituitary, and dentate gyrus granule neurons (alpha1H), and thalamic reticular neurons (alpha1I and alpha1H). Other regions of high expression included the Purkinje cell layer of the cerebellum, the bed nucleus of the stria terminalis, the claustrum (alpha1G), the olfactory tubercles (alpha1H and alpha1I), and the subthalamic nucleus (alpha1I and alpha1G). Some neurons expressed high levels of all three genes, including hippocampal pyramidal neurons and olfactory granule cells. Many brain regions showed a predominance of labeling for alpha1G, including the amygdala, cerebral cortex, rostral hypothalamus, brainstem, and spinal cord. Exceptions included the basal ganglia, which showed more prominent labeling for alpha1H and alpha1I, and the olfactory bulb, the hippocampus, and the caudal hypothalamus, which showed more even levels of all three transcripts. Our results are consistent with the hypothesis that differential gene expression underlies pharmacological and physiological heterogeneity observed in neuronal T-type calcium currents, and they provide a molecular basis for the study of T-type channels in particular neurons.

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

“…Similarly, these channels can be distinguished at the single-channel level by their conductance for Ba 2ϩ , and again, pituitary T-type currents have been clearly identified (203). In situ hybridization studies suggest all three Ca v 3 isoforms are expressed, although Ca v 3.2 was the predominant isoform detected (393). Consistent with this result, T-type currents were reported to be nickel sensitive, with 80% of the current blocked by 100 M NiCl 2 (240).…”

“…This hypothesis was supported by the cloning of T-type channels that differed in this property; Ca v 3.1 and 3.2 display fast inactivation, while Ca v 3.3 displays slowly inactivating currents. Notably, Ca v 3.3 mRNA is expressed in the same brain regions as the slow currents (177,228,393). Excluding these cases, the average inactivation from 22 studies is 20 ms.…”

Molecular Identity and Functional Properties of a Novel T-Type Ca2+ Channel Cloned From the Sensory Epithelia of the Mouse Inner Ear

“…Tissue-specific localization of T-type Ca 2ϩ channels has prompted the suggestion that the channel subtypes play unique roles that cannot be compensated by other channels (Talley et al 1999). Because mibefradil inhibits cell proliferation in vascular tissues and there appears to be robust expression of T-type current as cells transition from G0 to G1 and S-phase, the possibility that T-type channels could be involved in regulating cell proliferation has been raised (Bertolesi et al 2003).…”

Actions of U-92032, a T-Type Ca2+ Channel Antagonist, Support a Functional Linkage Between I T and Slow Intrathalamic Rhythms

“…Two older classes of drugs used to treat absence epilepsy, benzodiazepines and succinimides, apparently work through these mechanisms; however, improved drugs with greater efficacy and target specificity should be possible. With the recent cloning of three T-channel genes (␣1G, H, and I) and the finding that a1G is the primary T-channel gene expressed in thalamus (Talley et al 1999), it may be possible to produce a subunitspecific, and therefore location-specific, block of I T in those suffering from absence epilepsy. We believe the present findings of a clear, and complete, block of T-channels by U-92032 associated with a strong disruption of absence-like rhythmicity will justify further efforts to exploit a T-channel-dependent hypothesis of absence epilepsy in the pursuit of new therapies.…”