title: The upregulation of α2δ-1 subunit modulates activity-dependent Ca2+ signals in sensory neurons.
abstract: As auxiliary subunits of voltage-gated Ca(2+) channels, the α2δ proteins modulate membrane trafficking of the channels and their localization to specific presynaptic sites. Following nerve injury, upregulation of the α2δ-1 subunit in sensory dorsal root ganglion neurons contributes to the generation of chronic pain states; however, very little is known about the underlying molecular mechanisms. Here we show that the increased expression of α2δ-1 in rat sensory neurons leads to prolonged Ca(2+) responses evoked by membrane depolarization. This mechanism is coupled to CaV2.2 channel-mediated responses, as it is blocked by a ω-conotoxin GVIA application. Once initiated, the prolonged Ca(2+) transients are not dependent on extracellular Ca(2+) and do not require Ca(2+) release from the endoplasmic reticulum. The selective inhibition of mitochondrial Ca(2+) uptake demonstrates that α2δ-1-mediated prolonged Ca(2+) signals are buffered by mitochondria, preferentially activated by Ca(2+) influx through CaV2.2 channels. Thus, by controlling channel abundance at the plasma membrane, the α2δ-1 subunit has a major impact on the organization of depolarization-induced intracellular Ca(2+) signaling in dorsal root ganglion neurons.
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom m.d'arco@ucl.ac.uk a.dolphin@ucl.ac.uk.
authors: Marianna
authors: M
authors: D'Arco
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors: Wojciech
authors: W
authors: Margas
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom.
authors: John S
authors: JS
authors: Cassidy
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom m.d'arco@ucl.ac.uk a.dolphin@ucl.ac.uk.
authors: Annette C
authors: AC
authors: Dolphin
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009543:Nifedipine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
chemical_list: C503279:Cacna1b protein, rat; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D004791:Enzyme Inhibitors; D007211:Indoles; D014404:Tubulin; C462941:beta3 tubulin, mouse; C032456:antimycin; D000968:Antimycin A; D011189:Potassium Chloride; D020866:omega-Conotoxin GVIA; D009543:Nifedipine; D002118:Calcium; C000543:cyclopiazonic acid