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Endogenous Adenosine Reduces Glutamatergic Output From Rods Through Activation of A₂-Like Adenosine Receptors

Department of Pharmacology and Department of Ophthalmology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5540

Submitted 13 August 2002; accepted in final form 10 March 2003

Adenosine is released from retina in darkness; photoreceptors possess A₂ adenosine receptors, and A₂ agonists inhibit L-type Ca²⁺ currents (I_Ca) in rods. We therefore investigated whether A₂ agonists inhibit rod inputs into second-order neurons and whether selective antagonists to A₁, A_2A, or A₃ receptors prevent Ca²⁺ influx through rod I_Ca. [Ca²⁺]_i changes in rods were assessed with fura-2. I_Ca in rods and light responses of rods and second-order neurons were recorded using perforated patch-clamp techniques in the aquatic tiger salamander retinal slice preparation. Consistent with earlier results using the A₂ agonist N⁶-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (DPMA), the A_2A agonist CGS-21680 significantly inhibited I_Ca and depolarization-evoked [Ca²⁺]_i increases in rods. The A₁ antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and A_2A antagonist, ZM-241385, but not the A₃ antagonist, VUF-5574, inhibited effects of adenosine on Ca²⁺ influx in rods. DPCPX and ZM-241385 also inhibited effects of CGS-21680, suggesting they both act at A_2A receptors. Both A₂ agonists, CGS-21680 and DPMA, reduced light-evoked currents in second-order neurons but not light-evoked voltage responses of rods, suggesting that activation of A₂ receptors inhibits transmitter release from rods. The inhibitory effects of CGS-21680 on both depolarization-evoked Ca²⁺ influx and light-evoked currents in second-order neurons were antagonized by ZM-241385. By itself, ZM-241385 enhanced the light-evoked currents in second-order neurons, suggesting that endogenous levels of adenosine inhibit transmitter release from rods. The effects of these drugs suggest that endogenous adenosine activates an A₂-like adenosine receptor on rods leading to inhibition of I_Ca, which in turn inhibits L-glutamate release from rod photoreceptors.

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