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J Neurosci. 2009 Sep 9;29(36):11237-45. doi: 10.1523/JNEUROSCI.2836-09.2009.

Adenosine-evoked hyperpolarization of retinal ganglion cells is mediated by G-protein-coupled inwardly rectifying K+ and small conductance Ca2+-activated K+ channel activation.

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  • 1Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.


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 A(1) 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 Ca(2+) 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 A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) but was unaffected by A(2a), A(2b), and A(3) antagonists, indicating that the response was mediated entirely by A(1) 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 Ca(2+) and was blocked by IP(3) receptor antagonists and depletion of internal Ca(2+) stores, suggesting that A(1) receptor activation leads to an increase in IP(3), which then elevates intracellular Ca(2+) and activates SK channels. This A(1)-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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