α2δ-3 Is Required for Rapid Transsynaptic Homeostatic Signaling.
The homeostatic modulation of neurotransmitter release, termed presynaptic homeostatic potentiation (PHP), is a fundamental type of neuromodulation, conserved from Drosophila to humans, that stabilizes information transfer at synaptic connections throughout the nervous system. Here, we demonstrate that α2δ-3, an auxiliary subunit of the presynaptic calcium channel, is required for PHP. The α2δ gene family has been linked to chronic pain, epilepsy, autism, and the action of two psychiatric drugs: gabapentin and pregabalin. We demonstrate that loss of α2δ-3 blocks both the rapid induction and sustained expression of PHP due to a failure to potentiate presynaptic calcium influx and the RIM-dependent readily releasable vesicle pool. These deficits are independent of α2δ-3-mediated regulation of baseline calcium influx and presynaptic action potential waveform. α2δ proteins reside at the extracellular face of presynaptic release sites throughout the nervous system, a site ideal for mediating rapid, transsynaptic homeostatic signaling in health and disease.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Tingting
T
Wang
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Ryan T
RT
Jones
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Jenna M
JM
Whippen
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: graeme.davis@ucsf.edu.
Graeme W
GW
Davis
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019843:Archaeal Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D004533:Egtazic Acid / Q000494:pharmacology; D004843:Epistasis, Genetic / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D020692:rab3 GTP-Binding Proteins / Q000378:metabolism; D017494:Proton Pumps
D019843:Archaeal Proteins; D002118:Calcium; D015220:Calcium Channels; D029721:Drosophila Proteins; D004533:Egtazic Acid; D020692:rab3 GTP-Binding Proteins; C577877:RIM protein, Drosophila; C055476:archaerhodopsin protein, Archaea; D017494:Proton Pumps
Ca(V)2.1; autism; calcium channel; epilepsy; homeostatic plasticity; neuromuscular junction; neuropathic pain; presynaptic calcium influx; readily releasable vesicle pool; schizophrenia; synaptic homeostasis; synaptic transmission; α2δ-3