Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors.
Endogenous polyamines profoundly affect the activity of various ion channels, including that of calcium-permeable AMPA-type glutamate receptors (CP-AMPARs). Here we show that stargazin, a transmembrane AMPAR regulatory protein (TARP) known to influence transport, gating and desensitization of AMPARs, greatly reduces block of CP-AMPARs by intracellular polyamines. By decreasing CP-AMPAR affinity for cytoplasmic polyamines, stargazin enhances the charge transfer following single glutamate applications and eliminates the frequency-dependent facilitation seen with repeated applications. In cerebellar stellate cells, which express both synaptic CP-AMPARs and stargazin, we found that the rectification and unitary conductance of channels underlying excitatory postsynaptic currents were matched by those of recombinant AMPARs only when the latter were associated with stargazin. Taken together, our observations establish modulatory actions of stargazin that are specific to CP-AMPARs, and suggest that during synaptic transmission the activity of such receptors, and thus calcium influx, is fundamentally changed by TARPs.
Soto
David
D
Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
Coombs
Ian D
ID
Kelly
Leah
L
Farrant
Mark
M
Cull-Candy
Stuart G
SG
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D002531:Cerebellum / Q000166:cytology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011073:Polyamines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology*; D013096:Spermine / Q000494:pharmacology; D014162:Transfection
C491912:CACNG2 protein, human; D015220:Calcium Channels; D011073:Polyamines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C492973:alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype glutamate receptor, human; C104724:glutamate receptor ionotropic, AMPA 4; D013096:Spermine; D018698:Glutamic Acid; D002118:Calcium