Role of Hippocampal Ca<sub>v</sub>1.2 Ca<sup>2+</sup>Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Moosmang, Sven; Haider, Nicole; Klugbauer, Norbert; Adelsberger, Helmuth; Langwieser, Nicolas; Müller, Jochen; Stieß, Michael; Marais, Eise; Schulla, Verena; Lacinová, Ľubica; Goebbels, Sandra; Nave, Klaus Armin; Storm, Daniel R.; Hofmann, Franz; Kleppisch, Thomas

doi:10.1523/jneurosci.1531-05.2005

Cited by 393 publications

(393 citation statements)

References 77 publications

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“…CaMKII has been reported to stimulate the activity of recombinant CaV3.2 channels by phosphorylating the cytoplasmic linker connecting IIS6 to IIIS1 (24), but it had no effect on channel open time. Therefore, given the increasing importance of CaMKII, calcineurin, and dihydropyridine-sensitive calcium channels in neuronal plasticity and gene regulation (25)(26)(27)(28)(29), our hypothesis, which is consistent with newer structural data emphasizing the importance of the S6 helices in gating (30), provides a simple, testable mechanism for integrating many old and new observations on calcium channel regulation by calcium and reversible protein phosphorylation.…”

Section: Discussionsupporting

confidence: 82%

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Erxleben

Liao

Gentile

et al. 2006

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

105

116

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Calcium channels in the plasma membrane rarely remain open for much more than a millisecond at any one time, which avoids raising intracellular calcium to toxic levels. However, the dihydropyridinesensitive calcium channels of the CaV1 family, which selectively couple electrical excitation to endocrine secretion, cardiovascular contractility, and neuronal transcription, have a unique second mode of gating, ''mode 2,'' that involves frequent openings of much longer duration. Here we report that two human conditions, cyclosporin neurotoxicity and Timothy syndrome, increase mode 2 gating of the recombinant rabbit CaV1.2 channel. In each case, mode 2 gating depends on a Ser residue at the cytoplasmic end of the S6 helix in domain I (Ser-439, Timothy syndrome) or domain IV (Ser-1517, cyclosporin). Both Ser reside in consensus sequences for type II calmodulin-dependent protein kinase. Pharmacologically inhibiting type II calmodulin-dependent protein kinase or mutating the Ser residues to Ala prevents the increase in mode 2 gating. We propose that aberrant phosphorylation, or ''phosphorylopathy,'' of the CaV1.2 channel protein contributes to the excitotoxicity associated with Timothy syndrome and with chronic cyclosporin treatment of transplant patients.calcium͞calmodulin-dependent protein kinase type II ͉ calcineurin ͉ dihydropyridine ͉ excitotoxicity

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Section: Discussionsupporting

confidence: 82%

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Erxleben

Liao

Gentile

et al. 2006

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

105

116

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“…It has been shown that the LTCC is involved in NMDA receptor-independent LTP and spatial memory formation in mouse behavioral tests (100). As predicted by this established role for the LTCC in LTP and memory formation, we found that long-term memory in mutant presenilin flies was specifically affected during recovery from stress.…”

Section: Discussionsupporting

confidence: 78%

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons

et al. 2006

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It has been shown that presenilin is involved in maintaining Ca 2؉ homeostasis in neurons, including regulating endoplasmic reticulum (ER) Ca 2؉ storage. From studies of primary cultures and cell lines, however, its role in stress-induced responses is still controversial. In the present study we analyzed the effects of presenilin mutations on membrane currents and synaptic functions in response to stress using an in vivo preparation. We examined voltage-gated K ؉ and Ca 2؉ currents at the Drosophila larval neuromuscular junction (NMJ) with voltage-clamp recordings. Our data showed that both currents were generally unaffected by loss-of-function or Alzheimer's disease (AD) -associated presenilin mutations under normal or stress conditions induced by heat shock (HS) or ER stress. In larvae expressing the mutant presenilins, prolonged Ca 2؉ tail current, reflecting slower deactivation kinetics of Ca 2؉ channels, was observed 1 day after stress treatments were terminated. It was further demonstrated that the L-type Ca 2؉ channel was specifically affected under these conditions. Moreover, synaptic plasticity at the NMJ was reduced in larvae expressing the mutant presenilins. At the behavioral level, memory in adult flies was impaired in the presenilin mutants 1 day after HS. The results show that presenilin function is important during the poststress period and its impairment contributes to memory dysfunction observed during adaptation to normal conditions after stress. Our findings suggest a new stress-related mechanism by which presenilin may be implicated in the neuropathology of

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“…These observations indicate that CACNA1C may play a role in NMDA receptor‐dependent signaling and in synaptic plasticity in the hippocampus. In addition to ASD, SNPs in CACNA1C gene are linked to psychiatric disorders including schizophrenia and bipolar disorder (Li et al., 2015; Moosmang et al., 2005). In a large GWAS, two genes encoding the α 1 subunit of calcium channel ( CACNA1C) and its regulatory β 2 subunit ( CACNB2) were strongly linked to psychiatric disorders and ASD (Cross‐Disorder Group of the Psychiatric Genomics Consortium, 2013).…”

Section: Reviewmentioning

confidence: 99%

Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Cited by 393 publications

References 77 publications

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons

Autism throughout genetics: Perusal of the implication of ion channels

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Role of Hippocampal Cav1.2 Ca2+Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory

Cited by 393 publications

References 77 publications

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Cyclosporin and Timothy syndrome increase mode 2 gating of CaV1.2 calcium channels through aberrant phosphorylation of S6 helices

Differential behavioral state-dependence in the burst properties of CA3 and CA1 neurons

Autism throughout genetics: Perusal of the implication of ion channels

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Role of Hippocampal Ca_v1.2 Ca²⁺Channels in NMDA Receptor-Independent Synaptic Plasticity and Spatial Memory