| Gain of function in FHM-1 Ca(V)2.1 knock-in mice is related to the shape of the action potential. | |
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MedLine Citation:
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PMID: 20484531 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Familial hemiplegic migraine type-1 FHM-1 is caused by missense mutations in the CACNA1A gene that encodes the alpha(1A) pore-forming subunit of Ca(V)2.1 Ca(2+) channels. We used knock-in (KI) transgenic mice harboring the pathogenic FHM-1 mutation R192Q to study neurotransmission at the calyx of Held synapse and cortical layer 2/3 pyramidal cells (PCs). Using whole cell patch-clamp recordings in brain stem slices, we confirmed that KI Ca(V)2.1 Ca(2+) channels activated at more hyperpolarizing potentials. However, calyceal presynaptic calcium currents (I(pCa)) evoked by presynaptic action potentials (APs) were similar in amplitude, kinetic parameters, and neurotransmitter release. Ca(V)2.1 Ca(2+) channels in cortical layer 2/3 PCs from KI mice also showed a negative shift in their activation voltage. PCs had APs with longer durations and smaller amplitudes than the calyx of Held. AP-evoked Ca(2+) currents (I(Ca)) from PCs were larger in KI compared with wild-type (WT) mice. In contrast, when I(Ca)was evoked in PCs by calyx of Held AP waveforms, we observed no amplitude differences between WT and KI mice. In the same way, Ca(2+) currents evoked at the presynaptic terminals (I(pCa))of the calyx of Held by the AP waveforms of the PCs had larger amplitudes in R192Q KI mice that in WT. These results suggest that longer time courses of pyramidal APs were a key factor for the expression of a synaptic gain of function in the KI mice. In addition, our results indicate that consequences of FHM-1 mutations might vary according to the shape of APs in charge of triggering synaptic transmission (neurons in the calyx of Held vs. excitatory/inhibitory neurons in the cortex), adding to the complexity of the pathophysiology of migraine. |
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Authors:
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Carlota González Inchauspe; Francisco J Urbano; Mariano N Di Guilmi; Ian D Forsythe; Michel D Ferrari; Arn M J M van den Maagdenberg; Osvaldo D Uchitel |
Publication Detail:
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Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't Date: 2010-05-19 |
Journal Detail:
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Title: Journal of neurophysiology Volume: 104 ISSN: 1522-1598 ISO Abbreviation: J. Neurophysiol. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-08 Completed Date: 2011-01-07 Revised Date: 2011-08-01 |
Medline Journal Info:
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Nlm Unique ID: 0375404 Medline TA: J Neurophysiol Country: United States |
Other Details:
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Languages: eng Pagination: 291-9 Citation Subset: IM |
Affiliation:
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Instituto de Fisiología, Biología Molecular y Neurociencias, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Action Potentials
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physiology* Animals Calcium Channels / physiology* Cerebral Cortex / cytology, metabolism Electric Stimulation Electrophysiological Phenomena Excitatory Postsynaptic Potentials / physiology Humans Mice Mice, Inbred C57BL Mice, Transgenic Migraine Disorders / genetics, metabolism Migraine with Aura / genetics*, physiopathology Neurons, Afferent / physiology Neurotransmitter Agents / metabolism Patch-Clamp Techniques Pyramidal Cells / physiology Synapses / physiology Synaptic Transmission / physiology |
| Grant Support | |
ID/Acronym/Agency:
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RM36 046//Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/CACNA1A protein, human; 0/Calcium Channels; 0/Neurotransmitter Agents |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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