Adenosine A3 receptors potentiate hippocampal calcium current by a PKA-dependent/PKC-independent pathway

The modulation of high-threshold Ca current (I(Ca)) by adenosine receptors was studied using the voltage clamp method on acutely dissociated guinea pig hippocampal CA3 pyramidal neurons. When these neurons were exposed to adenosine in the presence of A1, A2a and A2b receptor antagonists, I(Ca) potentiation occurred at test potentials of -10 mV, but not at -40 mV. Similar potentiation also occurred using the A3 agonist N6-2-(4-aminophenyl)ethyl-adenosine (APNEA), either alone or in the presence of A1 and A2 antagonists. The putative A4 agonist 2-phenylaminoadenosine (CV-1808; Cornfield et al., 1992) did not potentiate I(Ca) at four concentrations tested between 25 nM and 2500 nM. K0.5 for the APNEA-induced potentiation was 25.4 nM, comparable to that determined in binding studies for the cloned receptor (15.5 nM; Zhou et al., 1992). I(Ca) potentiation by APNEA was blocked by intracellular application of WIPTIDE, a PKA inhibitor (p < 0.001), but was not affected by protein kinase C (PKC) inhibitor peptide (19-36). These results indicate that: (1) A3 receptor activation can significantly potentiate I(Ca), and (2) because the A3 receptor has been linked to down-regulation of adenylyl cyclase (Zhou et al., 1992), PKA appears to be negatively coupled to I(Ca).