Linking Channels and Pumps

Science Signaling  14 Apr 2009:
Vol. 2, Issue 66, pp. ec128
DOI: 10.1126/scisignal.266ec128

Trafficking of AMPA-type glutamate receptors (AMPARs, ligand-gated ion channels permeable to Na+) at excitatory synapses provides a well-known mechanism for the activity-dependent modulation of synaptic efficacy; the possible contribution of activity-dependent regulation of total AMPAR abundance to synaptic function, however, is less clear. Noting that neuronal activity leads to Na+ influx through AMPARs and during action potentials, Zhang et al. explored the role of the Na,K-ATPase (NKA)—which extrudes excess Na+—in regulating AMPAR-mediated synaptic transmission. Immunofluorescence analysis of cultured rat cortical neurons indicated that NKA colocalized with AMPARs at synapses, a finding confirmed by identification of abundant NKA in rat brain synaptosomes, and a combination of coimmunoprecipitation and pull-down assays indicated that the α1 subunit of NKA interacted with the AMPAR GluR2 subunit. Inhibition of NKA activity with ouabain (or other manipulations) led to a specific decrease of AMPAR abundance, which was apparent within 30 minutes and became more pronounced with sustained inhibition. Pharmacological analysis indicated that the ouabain-mediated decrease in AMPAR abundance was independent of protein synthesis and was mediated by proteasomal degradation. After observing that ouabain elicited membrane depolarization and transient high-frequency firing, the authors used a combination of ion substitution and pharmacological analysis to show that ouabain-mediated AMPAR degradation depended on Na+ influx, particularly influx through AMPARs. Ouabain-mediated AMPAR degradation also required AMPAR internalization and was associated with a decrease in AMPAR-mediated synaptic transmission that persisted long after ouabain washout. The authors raise the intriguing possibilities that Na+ acts as a second messenger to elicit AMPAR degradation and that endogenous NKA inhibitors may play a physiological—or pathophysiological—role in regulating synaptic strength.

D. Zhang, Q. Hou, M. Wang, A. Lin, L. Jarzylo, A. Navis, A. Raissi, F. Liu, H.-Y. Man, Na,K-ATPase activity regulates AMPA receptor turnover through proteasome-mediated proteolysis. J. Neurosci. 29, 4498–4511 (2009). [Abstract] [Full Text]