N-Type Calcium Channel α_1BSubunit (Ca_V2.2) Knock-Out Mice Display Hyperactivity and Vigilance State Differences

Abstract

Differential properties of voltage-dependent Ca2+ channels have been primarily ascribed to the alpha1 subunit, of which 10 different subtypes are currently known. For example, channels that conduct the N-type Ca2+ current possess the alpha1B subunit (Cav2.2), which has been localized, inter alia, to the piriform cortex, hippocampus, hypothalamus, locus coeruleus, dorsal raphe, thalamic nuclei, and granular layer of the cortex. Some of these regions have been previously implicated in metabolic and vigilance state control, and selective block of the N-type Ca2+ channel causes circadian rhythm disruption. In this study of Cav2.2-/- knock-out mice, we examined potential differences in feeding behavior, spontaneous locomotion, and the sleep-wake cycle. Cav2.2-/- mice did not display an overt metabolic phenotype but were hyperactive, demonstrating a 20% increase in activity under novel conditions and a 95% increase in activity under habituated conditions during the dark phase, compared with wild-type littermates. Cav2.2-/- mice also displayed vigilance state differences during the light phase, including increased consolidation of rapid-eye movement (REM) sleep and increased intervals between non-REM (NREM) and wakefulness episodes. EEG spectral power was increased during wakefulness and REM sleep and was decreased during NREM sleep in Cav2.2-/- mice. These results indicate a role of the N-type Ca2+ channel in activity and vigilance state control, which we interpret in terms of effects on neurotransmitter release.

IA Channels Encoded by Kv1.4 and Kv4.2 Regulate Neuronal Firing in the Suprachiasmatic Nucleus and Circadian Rhythms in Locomotor Activity

“…In addition, the 0.5 h shortening of the period of circadian rhythms in locomotor activity of mice lacking either Kv1.4 or Kv4.2 contrasts with the recently reported 0.5 h lengthening of the period of circadian behavior in mice lacking one copy of Scn1a, which encodes the voltage-gated sodium channel ␣ subunit, Nav1.1 (Han et al, 2012). The results here also contrast markedly with the results of several previous studies conducted on mice with other channel deficiencies, including mice lacking the large conductance, Ca 2ϩ and voltage-dependent, BK (Kcnma1); K ϩ channel subunit (Meredith et al, 2006); the voltage-gated Ca 2ϩ channel subunit, Cav2.2 (Cacna1b) (Beuckmann et al, 2003); or the Kv channel subunits, Kv3.1 and Kv3.2 (Kcnc1 and Kcnc2) (Kudo et al, 2011). In contrast with the findings here for Kv1.4…”

Deletion of N-Type Calcium Channels Alters Ethanol Reward and Reduces Ethanol Consumption in Mice

“…We also monitored baseline 24 hr water consumption by allowing mice access to two water bottles. No genotypic differences were seen (data not shown), consistent with a previous report that water and food consumption are normal in Ca v 2.2 null mice (Beuckmann et al, 2003).…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…In contrast with Ca V 2.1 null mice, Ca V 2.2 deficiency leads to only mild consequences, which include reduced pain hypersensitivity in models of inflammatory and neuropathic pain (Hatakeyama et al, 2001;Kim et al, 2001a;Saegusa et al, 2001), hyperactivity (Beuckmann et al, 2003), reduced anxiety (Saegusa et al, 2001), a reduction of voluntary alcohol intake (Newton et al, 2004), and problems with blood pressure control . The effects of Ca V 2.2 channel deletion on pain are consistent with the notion that Ca V 2.2 channels are critical for neurotransmitter release from afferent terminals in the spinal dorsal horn (for review, see Bourinet et al, 2014), and these findings validate Ca V 2.2 channels as potential targets for analgesics.…”