Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

Dragicevic, Elena; Poetschke, Christina; Duda, Johanna; Schlaudraff, Falk; Lammel, Stephan; Schiemann, Julia; Fauler, Michael; Hetzel, Andrea; Watanabe, Masahiko; Luján, Rafael; Malenka, Robert C.; Striessnig, Jörg; Liss, Birgit

doi:10.1093/brain/awu131

Cited by 107 publications

(148 citation statements)

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“…For example, a particularly high relative expression of short splice variants is observed in dopamine neurons in the Substantia nigra [35]. Splice-variant dependent mutational effects have also been reported for other voltage-gated Ca 2+ channels.…”

Section: Discussionmentioning

confidence: 99%

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

et al. 2018

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Recently, we and others identified somatic and germline de novo gain-of-function mutations in CACNA1D, the gene encoding the α1-subunit of voltage-gated Cav1.3 Ca2+-channels. While somatic mutations identified in aldosterone producing adenomas (APAs) underlie treatment-resistant hypertension, germline CACNA1D mutations are associated with a neurodevelopmental disorder characterized by a wide symptomatic spectrum, including autism spectrum disorder. The number of newly identified CACNA1D missense mutations is constantly growing, but their pathogenic potential is difficult to predict in silico, making functional studies indispensable to assess their contribution to disease risk.Here we report the functional characterization of previously identified CACNA1D APA mutations F747L and M1354I using whole-cell patch-clamp electrophysiology upon recombinant expression in tsA-201 cells. We also investigated if alternative splicing of Cav1.3 affects the aberrant gating of the previously characterized APA mutation R990H and two mutations associated with autism spectrum disorder (A479G and G407R). Splice-variant dependent gating changes are of particular interest for germline mutations, since the relative expression of Cav1.3 splice variants differs across different tissues and within brain regions and might therefore result in tissue-specific phenotypes. Our data revealed a complex gain-of-function phenotype for APA mutation F747L confirming its pathogenic role. Furthermore, we found splice-variant dependent gating changes in R990H, A749G and G407R. M1354I did not change channel function of Cav1.3 splice variants and should therefore be considered a rare non-pathogenic variant until further proof for its pathogenicity is obtained. Our new findings together with previously published data allow classification of pathogenic CACNA1D mutations into four categories based on prototypical functional changes.

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Section: Discussionmentioning

confidence: 99%

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

et al. 2018

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“…UV-LMD and RT of mRNA from retrobead-labeled neurons, as well as multiplex-nested PCR and quantitative real-time PCR (qPCR), were performed essentially as previously described (54,55). The mRNA values are given with respect to a relative cDNA standard, derived from mouse midbrain tissue.…”

Section: Methodsmentioning

confidence: 99%

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

Krabbe

Duda

Schiemann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.ventral tegmental area | dopamine D2 receptor | burst activity | NMDA receptor | schizophrenia D eficits in cognition and motivation are core features of schizophrenia (1, 2). These symptoms are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as a diagnostic criterion for schizophrenia spectrum disorder (3) and have a significant impact on patients' overall functioning and quality of life (4, 5). Currently, there are no effective treatments for these disabling aspects of the disease. Therefore, a high priority in the study of schizophrenia is to increase our understanding of the neurobiology of cognitive and motivational deficits. The midbrain dopamine (DA) system affects cognition and motivation in healthy subjects. It includes DA neurons of the ventral tegmental area (VTA), projecting to prefrontal cortex (PFC) and limbic areas (e.g., ventral striatum), and DA neurons of the substantia nigra (SN), projecting to the dorsal striatum (6). Involvement of the midbrain DA system is strongly implicated in both the cognitive and motivational deficits observed in schizophrenia (7,8). Moreover, it is well documented that the DA system is altered in patients with schizophrenia (reviewed in refs. 9, 10).To model the increase in striatal DA D2 receptor (D2R) activity observed in patients with schizophrenia, we previously generated transgenic mice that selectively and reversibly overexpress D2Rs in the striatum (D2R-OE mice) (11). In this model, expression of the transgenic D2Rs is restricted to the postsy...

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“…Ca V 1.1 and Ca V 1.4 a1 transcripts are not found at significant levels in the brain, although expression in a limited subset of neurons cannot be excluded (Sinnegger-Brauns et al, 2009). By contrast, in most electrically excitable cells, Ca V 1.2 and/or Ca V 1.3 are expressed and both isoforms are often even expressed in the same cell, such as in neurons (Olson et al, 2005;Chan et al, 2007;Dragicevic et al, 2014), adrenal chromaffin cells (Marcantoni et al, 2010), and sinoatrial node (SAN) and atrial cardiomyocytes (Mangoni et al, 2003). Both channels are required for normal brain function and serve different roles in the cardiovascular system and in endocrine functions.…”

Section: Ca V 1 Channel Familymentioning

confidence: 97%

“…Channel-bound calmodulin (CaM) and calmodulin kinase II (CaMKII) are essential biochemical elements decoding voltage-induced alterations in channel activity (Wheeler et al, 2008;Ma et al, 2013). Approximately 90% of the LTCCs in the brain are Ca V 1.2 and only 10% are Ca V 1.3 (Hell et al, 1993;Sinnegger-Brauns et al, 2009), and they often reside within the same neuron (Olson et al, 2005;Chan et al, 2007;Dragicevic et al, 2014).…”

Section: Ca V 1 Channel Familymentioning

confidence: 99%

“…In these permanently active neurons, they mediate activity-dependent dendritic Ca 2+ transients that contribute to oxidative stress. Transcripts for both Ca V 1.2 and Ca V 1.3 have been detected in these cells (Chan et al, 2007;Dragicevic et al, 2014). LTCCs appear to have only a minor stabilizing role for pacemaking itself (Guzman et al, 2009;Dragicevic et al, 2014), but Ca V 1.3 Ca 2+ channels regulate SNc firing rates through dopamine D2 autoreceptors activated by dendritic dopamine release in a negative feedback loop through activation of G protein-coupled K + channels (GIRKs) such as GIRK2 (KCNJ6) (Dragicevic et al, 2014).…”

Section: Ca V 1 Channel Familymentioning

confidence: 99%

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

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

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Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

Cited by 107 publications

References 70 publications

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

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

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Cav1.3 channels control D2-autoreceptor responses via NCS-1 in substantia nigra dopamine neurons

Cited by 107 publications

References 70 publications

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

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

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Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels

Gating defects of disease-causing de novo mutations in Ca_v1.3 Ca²⁺ channels