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The Journal of Neuroscience, September 9, 2009, 29(36):11237-11245; doi:10.1523/JNEUROSCI.2836-09.2009

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Cellular/Molecular
Adenosine-Evoked Hyperpolarization of Retinal Ganglion Cells Is Mediated by G-Protein-Coupled Inwardly Rectifying K⁺ and Small Conductance Ca²⁺-Activated K⁺ Channel Activation

Benjamin D. Clark, Zeb L. Kurth-Nelson, and Eric A. Newman

Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455

Correspondence should be addressed to Eric A. Newman, 6-145 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455. Email: ean{at}umn.edu

Adenosine is a neuromodulator that activates presynaptic receptors to regulate synaptic transmission and postsynaptic receptors to hyperpolarize neurons. Here, we report that adenosine-induced hyperpolarization of retinal ganglion cells is produced by the activation of A₁ receptors, which initiates a signaling cascade that activates G-protein-coupled inwardly rectifying K⁺ (GIRK) channels and small conductance Ca²⁺-activated K⁺ (SK) channels. Rat retinal ganglion cells were stimulated by focal ejection of the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA) while cell activity was monitored with whole-cell patch recordings and Ca²⁺ imaging. Focal ejections of NECA evoked outward currents in all cells tested and reduced light- and depolarization-induced spiking. The NECA-evoked current was abolished by the A₁ antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) but was unaffected by A_2a, A_2b, and A₃ antagonists, indicating that the response was mediated entirely by A₁ receptors. The GIRK channel blocker rTertiapin-Q diminished the NECA-evoked inhibitory current by 56 ± 12%, whereas the SK channel blocker apamin decreased the NECA-induced current by 42 ± 7%. The SK component of the NECA-evoked current coincided with an increase in intracellular Ca²⁺ and was blocked by IP₃ receptor antagonists and depletion of internal Ca²⁺ stores, suggesting that A₁ receptor activation leads to an increase in IP₃, which then elevates intracellular Ca²⁺ and activates SK channels. This A₁-mediated, prolonged SK channel activation has not been described previously. The coactivation of GIRK and SK channels represents a novel mechanism of adenosine-mediated neuromodulation that could contribute to the regulation of retinal ganglion cell activity.

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Received June 16, 2009; revised July 23, 2009; accepted Aug. 2, 2009.

Correspondence should be addressed to Eric A. Newman, 6-145 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455. Email: ean{at}umn.edu

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