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Evaluation of voltage-dependent calcium channel ? gene families identified several novel potential susceptible genes to schizophrenia.

ABSTRACT: Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (??-?1, ? -2/?, ?, and ?), the ? subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the ? subunit gene family to SCZ, we conducted a large-scale association study in Han Chinese individuals. The SNP rs17645023 located in the intergenic region of CACNG4 and CACNG5 was identified to be significantly associated with SCZ (OR?=?0.856, P?=?5.43?×?10(-5)). Similar results were obtained in the meta-analysis with the current SCZ PGC data (OR?=?0.8853). We also identified a two-SNP haplotype (rs10420331-rs11084307, P?=?1.4?×?10(-6)) covering the intronic region of CACNG8 to be significantly associated with SCZ. Epistasis analyses were conducted, and significant statistical interaction (OR?=?0.622, P?=?2.93?×?10(-6), Pperm?

SUBMITTER: Guan F

PROVIDER: S-EPMC4840350 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia.

Guan Fanglin F Zhang Tianxiao T Liu Xinshe X Han Wei W Lin Huali H Li Lu L Chen Gang G Li Tao T

Scientific reports 20160422

Voltage-gated L-type calcium channels (VLCC) are distributed widely throughout the brain. Among the genes involved in schizophrenia (SCZ), genes encoding VLCC subunits have attracted widespread attention. Among the four subunits comprising the VLCC (α - 1, α -2/δ, β, and γ), the γ subunit that comprises an eight-member protein family is the least well understood. In our study, to further investigate the risk susceptibility by the γ subunit gene family to SCZ, we conducted a large-scale associati ...[more]

PMID: 27102562

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Project description:L-type voltage-gated calcium channels (LTCCs) are implicated in several psychiatric disorders that are comorbid with alcoholism and involve amygdala dysfunction. Within the amygdala, the central nucleus (CeA) is critical in acute alcohol's reinforcing actions, and its dysregulation in human alcoholics drives their negative emotional state and motivation to drink. Here we investigated the specific role of CeA LTCCs in the effects of acute alcohol at the molecular, cellular physiology, and behavioral levels, and their potential neuroadaptation in alcohol-dependent rats. Alcohol increases CeA activity (neuronal firing rates and GABA release) in naive rats by engaging LTCCs, and intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence reduces CeA LTCC membrane abundance and disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. Collectively, our data indicate that alcohol dependence functionally alters the molecular mechanisms underlying the CeA's response to alcohol (from LTCC- to CRF1-driven). This mechanistic switch contributes to and reflects the prominent role of the CeA in the negative emotional state that drives excessive drinking.SIGNIFICANCE STATEMENT The central amygdala (CeA) plays a critical role in the development of alcohol dependence. As a result, much preclinical alcohol research aims to identify relevant CeA neuroadaptions that promote the transition to dependence. Here we report that acute alcohol increases CeA neuronal activity in naive rats by engaging L-type calcium channels (LTCCs) and that intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. This switch reflects the important role of the CeA in the pathophysiology of alcohol dependence and represents a new potential avenue for therapeutic intervention during the transition period.

Dataset Information

Evaluation of voltage-dependent calcium channel ? gene families identified several novel potential susceptible genes to schizophrenia.

Publications

Evaluation of voltage-dependent calcium channel γ gene families identified several novel potential susceptible genes to schizophrenia.

Similar Datasets

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