Chanki Kim

Deletion of N-type calcium channels alters ethanol reward and reduces ethanol consumption in mice

N-type calcium channels are modulated by acute and chronic ethanol exposure in vitro at concentrations known to affect humans, but it is not known whether N-type channels are important for behavioral responses to ethanol in vivo. Here, we show that in mice lacking functional N-type calcium channels, voluntary ethanol consumption is reduced and place preference is developed only at a low dose of ethanol. The hypnotic effects of ethanol are also substantially diminished, whereas ethanol-induced ataxia is mildly increased. These results demonstrate that N-type calcium channels modulate acute responses to ethanol and are important mediators of ethanol reward and preference.

A Blocker of N- and T-type Voltage-Gated Calcium Channels Attenuates Ethanol-Induced Intoxication, Place Preference, Self-Administration, and Reinstatement

There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.

Thalamic Ryanodine Receptors Are Involved in Controlling the Tonic Firing of Thalamocortical Neurons and Inflammatory Pain Signal Processing

Ryanodine receptors (RyRs) are highly conductive intracellular Ca2+ release channels which are widely expressed in the CNS. They rapidly increase the intracellular Ca2+ concentrations in neuronal cells in response to Ca2+ influx through voltage-gated Ca2+ channels. A previous study reported that RyRs were expressed in thalamocortical (TC) neurons, but their physiological function has remained elusive. Here, we show that the activation of RyRs in TC neurons in mice decreases their tonic firing rate while blocking them induces the opposite response. Furthermore, activation of RyRs in ventroposteriomedial/ventroposteriolateral nuclei reduces the behavioral responses to inflammatory pain and blocking them increases the responses. This study highlights the importance of the intracellular Ca2+ release via RyRs in controlling the excitability of TC neurons and in inflammatory pain signal processing in the thalamus.

Age-dependent gait abnormalities in mice lacking the Rnf170 gene linked to human autosomal-dominant sensory ataxia

Really interesting new gene (RING) finger protein 170 (RNF170) is an E3 ubiquitin ligase known to mediate ubiquitination-dependent degradation of type-I inositol 1,4,5-trisphosphate receptors (ITPR1). It has recently been demonstrated that a point mutation of RNF170 gene is linked with autosomal-dominant sensory ataxia (ADSA), which is characterized by an age-dependent increase of walking abnormalities, a rare genetic disorder reported in only two families. Although this mutant allele is known to be dominant, the functional identity thereof has not been clearly established. Here, we generated mice lacking Rnf170 (Rnf170(-/-)) to evaluate the effect of its loss of function in vivo. Remarkably, Rnf170(-/-) mice began to develop gait abnormalities in old age (12 months) in the form of asynchronous stepping between diagonal limb pairs with a fixed step sequence during locomotion, while age-matched wild-type mice showed stable gait patterns using several step sequence repertoires. As reported in ADSA patients, they also showed a reduced sensitivity for proprioception and thermal nociception. Protein blot analysis revealed that the amount of Itpr1 protein was significantly elevated in the cerebellum and spinal cord but intact in the cerebral cortex in Rnf170(-/-) mice. These results suggest that the loss of Rnf170 gene function mediates ADSA-associated phenotypes and this gives insights on the cure of patients with ADSA and other age-dependent walking abnormalities.

Chapter 14 Functional Diversity of Voltage‐Dependent Ca2+ Channels in Nociception: Recent Progress in Genetic Studies

Publisher Summary This chapter reviews the behavioral consequences in mice lacking diverse subunits of voltage‐dependent Ca 2+ channels (VDCCs) in response to various types of painful stimuli and compares these phenotypes with the data obtained from pharmacology‐based approaches. These collective studies from pharmacological and genetic approaches reveal that selective modulations of different VDCCs may provide novel therapeutic modalities for the treatment of various types of pain. VDCCs play a pivotal role in sensory processing, including nociception, by increasing the intracellular Ca 2+ concentration of neurons in response to excitation. Pain‐related behaviors in several VDCC knockout mice have been studied to yield significant progress in elucidating the physiological importance of various subtypes of VDCCs in pain transmission at the level of the organism. Sensory stimuli are relayed from the periphery to the cortex as a form of action potential by a series of the excitation of relay neurons. VDCCs are also involved in the regulation of neurotransmitter release, membrane excitability, electrical spiking behavior, and gene expression.