Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors.
The AMPA-type glutamate receptors mediate the majority of the fast excitatory synaptic transmission and critically contribute to synaptic plasticity in the brain, hence the existence of numerous trafficking proteins dedicated to regulation of their synaptic delivery and turnover. Stargazin (also termed gamma2) is a member of a recently identified protein family termed transmembrane AMPA receptor regulatory proteins (TARPs). TARPs physically associate with AMPA receptors and participate in their surface delivery and anchoring at the postsynaptic membrane. Here, we report that next to its trafficking roles, stargazin may also act as a positive allosteric modulator of AMPA receptor ion channel function. Coexpression of stargazin with AMPA receptor subunits, either in Xenopus oocytes or in human embryonic kidney 293 cells, significantly reduced receptor desensitization in response to glutamate. Receptor deactivation rates were also slowed, and the recovery from desensitization was accelerated. Structurally, based on the data showing a tight correlation between desensitization and the stability of the AMPA receptor intradimer interface, we propose that binding of stargazin may stabilize the receptor conformation. Functionally, our data suggest that AMPA receptors complexed with stargazin (and possibly also with other TARPs) at the postsynaptic membrane are significantly more responsive to synaptically released glutamate compared with AMPA receptors lacking stargazin/TARP interaction. The putative existence of such two states of synaptic AMPA receptors, with and without stargazin/TARP binding, may provide a novel mechanism for regulation of excitatory synaptic strength during development and/or in synaptic plasticity in the adult brain.
Priel
Avi
A
The Institute of Basic Dental Sciences, The Hebrew University-Hadassah Dental School, Jerusalem 91120, Israel.
Kolleker
Alexander
A
Ayalon
Gai
G
Gillor
Moshe
M
Osten
Pavel
P
Stern-Bach
Yael
Y
D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis / Q000502:physiology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D014982:Xenopus laevis
D015220:Calcium Channels; D018698:Glutamic Acid; D018091:Receptors, AMPA; C491912:CACNG2 protein, human