Studies on the ionic mechanism for the neuromodulatory actions of adenosine in the brain.
Although much evidence exists to support the modulation of neurotransmitter release by adenosine in both the central and peripheral nervous systems, the ionic mechanisms involved in this process are still not established. In our initial series of studies, the effects of adenosine analogs on depolarization-induced 45Ca influx into synaptosomes were examined, but no reduction in 45Ca uptake was observed in the presence of these agents, regardless of whether synaptosomes were depolarized by KCl or veratridine. The possibility that synaptosomal adenosine receptors are coupled directly to K+ channels and that an increase in K+ conductance is the primary ionic event initiated by adenosine was examined in resealed synaptic plasma membranes. We followed the movement of K+ through the use of the labeled lipophilic anion [35S]thiocyanate [( 35S]SCN-), which distributes across membranes according to the existing membrane potential. Both 2-chloroadenosine and adenosine-5'-cyclopropyl carboxamide produced dose-dependent increases in SCN- uptake, indicating enhanced K+ fluxes across the synaptic membranes. These effects of adenosine receptor agonists on membrane K+ conductance were blocked by receptor antagonists such as isobutylmethylxanthine. In addition, the placement of a K+-selective microelectrode in the caudate nuclei of intact, anesthetized rats revealed a substantial increase in the extracellular K+ concentration when adenosine was released onto the cells from a pipet in the assembly containing the ion-selective microelectrode. The results of these studies at both the membrane level and in the intact brain suggest that the initial event in the neuromodulatory actions of adenosine is an increase in the membrane conductance for K+ rather than inhibition of the voltage sensitive Ca2+ channels.
Michaelis
M L
ML
Center for Biomedical Research, University of Kansas 66046.
Johe
K K
KK
Moghadam
B
B
Adams
R N
RN
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015762:2-Chloroadenosine; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D008297:Male; D018377:Neurotransmitter Agents; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*; D013861:Thiocyanates / Q000378:metabolism; D014634:Valinomycin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology
D018377:Neurotransmitter Agents; D015221:Potassium Channels; D013861:Thiocyanates; D015762:2-Chloroadenosine; D014634:Valinomycin; D014701:Veratridine; D000241:Adenosine; D011188:Potassium; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine