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, Eric A. Newman

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33 Scopus citations


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 Ca 2+-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 A2a, A2b, 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 Ca 2+ stores, suggesting that A1 receptor activation leads to an increase in IP3 , which then elevates intracellular Ca 2+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.

Original languageEnglish (US)
Pages (from-to)11237-11245
Number of pages9
JournalJournal of Neuroscience
Issue number36
StatePublished - Sep 9 2009

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