CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease

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Abstract

One of the most consistent genetic findings to have emerged from bipolar disorder genome wide association studies (GWAS) is with CACNA1C, a gene that codes for the α1C subunit of the Cav1.2 voltage-dependent L-type calcium channel (LTCC). Genetic variation in CACNA1C have also been associated with depression, schizophrenia, autism spectrum disorders, as well as changes in brain function and structure in control subjects who have no diagnosable psychiatric illness. These data are consistent with a continuum of shared neurobiological vulnerability between diverse—Diagnostic and Statistical Manual (DSM) defined—neuropsychiatric diseases. While involved in numerous cellular functions, Cav1.2 is most frequently implicated in coupling of cell membrane depolarization to transient increase of the membrane permeability for calcium, leading to activation and, potentially, changes in intracellular signaling pathway activity, gene transcription, and synaptic plasticity. Cav1.2 is involved in the proper function of numerous neurological circuits including those involving the hippocampus, amygdala, and mesolimbic reward system, which are strongly implicated in psychiatric disease pathophysiology. A number of behavioral effects of LTCC inhibitors have been described including antidepressant-like behavioral actions in rodent models. Clinical studies suggest possible treatment effects in a subset of patients with mood disorders. We review the genetic structure and variation of CACNA1C, discussing relevant human genetic and clinical findings, as well as the biological actions of Cav1.2 that are most relevant to psychiatric illness.

Highlights

► Psychiatric disorders share overlapping genetic vulnerabilities. ► Genetic changes in CACNA1C are robustly associated with a diagnosis of diverse psychiatric disorders. ► Genetic changes in CACNA1C are associated with alterations in brain structure and function changes in normal subjects. ► Cav1.2, the protein coded for by CACNA1C, has important roles in many neurological circuits implicated in the pathophysiology of diverse psychiatric disorders.

Section snippets

CACNA1C in mental disorders

While a number of medications are used for the treatment of psychiatric disorders, the majority were developed based upon efficacy to reduce symptoms rather than to eliminate pathological processes. Current treatments are inadequate for many patients as recurrence is common and the full clinical effects are often not obtained until after months of treatment. Despite these well-known inadequacies, improvements have been slow in coming largely due to a dearth of understanding regarding

CACNA1C genetic variation

CACNA1C is located on the short arm of chromosome 12p13.3, spanning an approximately 6.45 Mb genomic region (Gene ID 775). The gene consists of at least 55 exons (Soldatov, 1994), which span an approximately 740 kb region. A number of SNPs in CACNA1C, concentrated within the large 328.5-kb intron 3, have been linked to psychiatric illness (Table 1), with limited information currently available regarding functional consequences. The locations of these SNPs within the gene are detailed in Fig. 2.

Cav1.2 calcium channel

The Cav1.2 α1C subunit consists of four repeating domains (I–IV), each with six transmembrane α helical segments (S1–S6) that are connected by intra- and extra-cellular loops (Abernethy and Soldatov, 2002, Mikami et al., 1989, Tanabe et al., 1987) as well as a long C-terminus and shorter N-tail that both point to the cytoplasm. In neurons of the central nervous system, Cav1.2 channels are located primarily in the postsynaptic dendritic processes and somata, and are distributed throughout the

Function of Cav1.2 in the brain circuits and behaviors of rodents

The importance of Cav1.2 channels in regulating the functions of brain circuits and behaviors has been shown through administration of LTCC agonists and antagonists, as well as using several genetic knockout approaches. A germline knockout of Cacna1c is embryonically lethal (Seisenberger et al., 2000), however conditional knockout and heterozygous mouse models have been successfully used. LTCCs have been found to play a role in behaviors mediated by the mesolimbic pathway. This pathway

Effects of CACNA1C on human brain function

Supporting the rodent data implicating Cav1.2 in basic brain function, a number of recent reports have associated a primary disease-associated SNP in CACNA1C, rs1006737, with variation in human brain function and structure in subjects who have no diagnosable psychiatric illness (Table 2). While polymorphisms in CACNA1C are significantly associated with bipolar disorder, depression, and schizophrenia, such genetic changes only increase probability of disease, and are not deterministic. Thus, a

L-type calcium channel antagonists in the treatment of psychiatric disease

LTCC antagonists are mainly used clinically for treating high blood pressure, angina, and abnormal heart rhythms. Chemically, they are represented by three different structural classes: dihydropyridines, benzothiazepines, and phenylalkylamines, which all act by binding to different sites on Cav1.2 and blocking the calcium current (Triggle, 1992). LTCC antagonists within the same structural class may vary in their affinity for the same calcium channel subtype, as well as for their penetration of

Conclusions

Underlying genetics are among the strongest risk factors for the development of mood disorders and schizophrenia, and there is shared genetic overlap between DSM-defined disorders including bipolar disorder, unipolar depression, and schizophrenia. This shared genetic overlap is coincident with shared environmental risk factors, as well as extensive overlap in neurobiology–as evidenced by biological markers and endophenotypes–and in efficacious treatments (Demjaha et al., 2011, Gottesman and

Acknowledgments

This work was supported by a NARSAD “Helen Lowenstein” Young Investigator Award and NIH MH093967 to TDG.

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