Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis.
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.
Eroglu
Cagla
C
Duke University Medical Center, Cell Biology Department, Durham, NC 27710, USA. c.eroglu@cellbio.duke.edu
Allen
Nicola J
NJ
Susman
Michael W
MW
O'Rourke
Nancy A
NA
Park
Chan Young
CY
Ozkan
Engin
E
Chakraborty
Chandrani
C
Mulinyawe
Sara B
SB
Annis
Douglas S
DS
Huberman
Andrew D
AD
Green
Eric M
EM
Lawler
Jack
J
Dolmetsch
Ricardo
R
Garcia
K Christopher
KC
Smith
Stephen J
SJ
Luo
Z David
ZD
Rosenthal
Arnon
A
Mosher
Deane F
DF
Barres
Ben A
BA
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
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