Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Sci. Signal., 14 April 2009
Vol. 2, Issue 66, p. ec128
[DOI: 10.1126/scisignal.266ec128]

EDITORS' CHOICE

Synapses Linking Channels and Pumps

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

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 {alpha}1 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]

Citation: E. M. Adler, Linking Channels and Pumps. Sci. Signal. 2, ec128 (2009).

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882