Na,K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis.
Neuronal activity largely depends on two key components on the membrane: the Na,K-ATPase (NKA) that maintains the ion gradients and sets the foundation of excitability, and the ionotropic glutamatergic AMPA receptors (AMPARs) through which sodium influx forms the driving force for excitation. Because the frequent sodium transients from glutamate receptor activity need to be efficiently extruded, a functional coupling between NKA and AMPARs should be a necessary cellular device for synapse physiology. We show that NKA is enriched at synapses and associates with AMPARs. NKA dysfunction induces a rapid reduction in AMPAR cell-surface expression as well as total protein abundance, leading to a long-lasting depression in synaptic transmission. AMPAR proteolysis requires sodium influx, proteasomal activity and receptor internalization. These data elucidate a novel mechanism by which NKA regulates AMPAR turnover and thereby synaptic strength and brain function.
Department of Biology, Boston University, 24 Cummington Street, Boston, MA 02215, USA.
Dawei
D
Zhang
Qingming
Q
Hou
Min
M
Wang
Amy
A
Lin
Larissa
L
Jarzylo
Allison
A
Navis
Aram
A
Raissi
Fang
F
Liu
Heng-Ye
HY
Man
D000818:Animals; D002478:Cells, Cultured; D006868:Hydrolysis; D010042:Ouabain / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism* / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism
D018091:Receptors, AMPA; D010042:Ouabain; D046988:Proteasome Endopeptidase Complex; D000254:Sodium-Potassium-Exchanging ATPase