title: Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis.
abstract: Synapses are asymmetric cellular adhesions that are critical for nervous system development and function, but the mechanisms that induce their formation are not well understood. We have previously identified thrombospondin as an astrocyte-secreted protein that promotes central nervous system (CNS) synaptogenesis. Here, we identify the neuronal thrombospondin receptor involved in CNS synapse formation as alpha2delta-1, the receptor for the anti-epileptic and analgesic drug gabapentin. We show that the VWF-A domain of alpha2delta-1 interacts with the epidermal growth factor-like repeats common to all thrombospondins. alpha2delta-1 overexpression increases synaptogenesis in vitro and in vivo and is required postsynaptically for thrombospondin- and astrocyte-induced synapse formation in vitro. Gabapentin antagonizes thrombospondin binding to alpha2delta-1 and powerfully inhibits excitatory synapse formation in vitro and in vivo. These findings identify alpha2delta-1 as a receptor involved in excitatory synapse formation and suggest that gabapentin may function therapeutically by blocking new synapse formation.
authors.affiliation: Duke University Medical Center, Cell Biology Department, Durham, NC 27710, USA. c.eroglu@cellbio.duke.edu
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Allen
authors.forename: Michael W
authors.initials: MW
authors.lastname: Susman
authors.forename: Nancy A
authors.initials: NA
authors.lastname: O'Rourke
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Park
authors.forename: Engin
authors.initials: E
authors.lastname: Ozkan
authors.forename: Chandrani
authors.initials: C
authors.lastname: Chakraborty
authors.forename: Sara B
authors.initials: SB
authors.lastname: Mulinyawe
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Annis
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Huberman
authors.forename: Eric M
authors.initials: EM
authors.lastname: Green
authors.forename: Jack
authors.initials: J
authors.lastname: Lawler
authors.forename: Ricardo
authors.initials: R
authors.lastname: Dolmetsch
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smith
authors.forename: Z David
authors.initials: ZD
authors.lastname: Luo
authors.forename: Arnon
authors.initials: A
authors.lastname: Rosenthal
authors.forename: Deane F
authors.initials: DF
authors.lastname: Mosher
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
mesh_terms: D000588:Amines / Q000494:pharmacology; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology; D000077206:Gabapentin; D051379:Mice; D055495:Neurogenesis; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000588:Amines; D018955:CD36 Antigens; C486060:Cacna2d1 protein, rat; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin