Adenosine-evoked hyperpolarization of retinal ganglion cells is mediated by G-protein-coupled inwardly rectifying K+ and small conductance Ca2+-activated K+ channel activation.
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.
Clark
Benjamin D
BD
Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Kurth-Nelson
Zeb L
ZL
Newman
Eric A
EA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000241:Adenosine / Q000494:pharmacology / Q000502:physiology*; D058907:Adenosine A1 Receptor Agonists; D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D043682:Receptor, Adenosine A1 / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000502:physiology*
D058907:Adenosine A1 Receptor Agonists; D024661:Potassium Channels, Inwardly Rectifying; D043682:Receptor, Adenosine A1; D043562:Receptors, G-Protein-Coupled; D051640:Small-Conductance Calcium-Activated Potassium Channels; D019830:Adenosine-5'-(N-ethylcarboxamide); D000241:Adenosine