Pertussis toxin reverses adenosine inhibition of neuronal glutamate release

Abstract

Adenosine and its analogues are potent inhibitors of synaptic activity in the central and peripheral nervous system^1,2. In the central nervous system (CNS), this appears to arise primarily by inhibition of presynaptic release of transmitters^3,4, including glutamate⁵, which is possibly the major excitatory transmitter in the brain. In addition, postsynaptic effects of adenosine have been reported which would also serve to reduce neurotransmission^6,7. The mechanism by which adenosine inhibits CNS neurotransmission is unknown, although it appears to exert its effect via an A₁ receptor^2,8 which in some systems is negatively coupled to adenylate cyclase⁹. In an attempt to elucidate the mechanism of inhibition, we have examined the effect of pertussis toxin (PTX) on the ability of the stable adenosine analogue (−)phenylisopropy-ladenosine (PIA) to inhibit glutamate release from cerebellar neurones maintained in primary culture. PTX, by ADP-ribosy-lating the nucleotide-binding protein N_i, prevents coupling of inhibitory receptors such as the A₁ receptor to adenylate cyclase¹⁰. As reported here, we found that PTX, as well as preventing inhibition of adenylate cyclase by PIA, also converts the PIA-induced inhibition of glutamate release to a stimulation. Our results suggest strongly that purinergic inhibitory modulation of transmitter release occurs by inhibition of adenylate cyclase.