A1 adenosine receptor-mediated modulation of neuronal ATP-sensitive K channels in rat substantia nigra

ATP-sensitive K (KATP) channels, widely expressed in cytoplasmic membranes of neurons, couple cell metabolism to excitability. They are considered to play important roles in controlling seizure activity during hypoxia and in neuroprotection against cell damage during hypoxia, ischemia and excitotoxicity. It is known that adenosine augments the opening of cardiac surface KATP channels by reducing the sensitivity of these channels to ATP blockade. We investigated whether a similar modulation occurs in neuronal channels. Whole cell voltage–clamp recordings were made using rat midbrain slices to record the membrane current and conductance in principal neurons of the substantia nigra pars compacta (SNc). When the pipette solution contained 1 mM ATP, the membrane current at − 60 mV and cellular conductance remained stable for at least 15 min. When slices were treated with (−)-N6-2-phenylisopropyl adenosine (R-PIA), a selective agonist for A1 adenosine receptors, in the same condition, the outward current developed slowly to the amplitude of 109.9 ± 26.6 pA, and conductance increased to 229 ± 50% of the baseline. These changes were strongly inhibited by 200 μM tolbutamide, a KATP channel blocker, suggesting that opening of KATP channels mediated these changes. Pretreatment with 8-cyclopentyltheophylline (CPT), a selective A1 adenosine receptor antagonist, abolished the outward current and conductance increases. Treatment of adenosine resulted in the similar changes sensitive to tolbutamide. These changes were abolished by CPT. These results suggest that activation of A1 adenosine receptors promotes the opening of KATP channels in principal neurons of the SNc by removing the blockade by ATP.