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Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637.
1. The role of adenosine receptors in reducing calcium currents (ICa) and in triggering presynaptic inhibition was studied using whole-cell patch-clamp techniques to record ICa and synaptic currents from the cell bodies of cultured rat hippocampal pyramidal neurones. Recordings of intracellular Ca2+ using the indicator dye Fura-2 were used to obtain further insights into the actions of adenosine agonists. 2. The adenosine analogue 2-chloroadenosine (2-CA) reduced ICa in these neurones. This action was also evident when Ba2+ was used as the charge carrier through Ca2+ channels. Adenosine also reduced the influx of Ca2+ into the cell body during a depolarizing voltage-clamp pulse as measured with Fura-2. The potency of various adenosine receptor agonists was as follows: cyclopentyladenosine greater than cyclohexyl-adenosine greater than or equal to R-phenylisopropyladenosine greater than 2-CA greater than S-phenylisopropyladenosine, consistent with the pharmacological profile of an A1 adenosine receptor. 3. The specific A1 receptor antagonist cyclopentyltheophylline (CPT) blocked the actions of 2-CA on ICa in a competitive fashion. 4. The actions of 2-CA on ICa were abolished by pre-incubation of cultured cells with pertussis toxin (PTX; 250 ng/ml). Intracellular dialysis with the GTP analogue GTP-gamma-S (guanosine-5'-O-(3-thiotriphosphate] enhanced the actions of 2-CA and rendered the response irreversible. 5. Excitatory postsynaptic currents (EPSCs) were recorded from pyramidal neurones under whole-cell voltage clamp by stimulating nearby neurones with an extracellular electrode. 2-CA potently and reversibly reduced the amplitude of EPSCs. This action was shown to be due to presynaptic inhibition of neurotransmitter release. 6. The order of potency of different adenosine agonists in reducing EPSCs was as follows: cyclopentyladenosine greater than cyclohexyladenosine greater than or equal to R-phenylisopropyladenosine greater than 2-CA greater than S-phenylisopropyladenosine. CPT inhibited the action of 2-CA in a competitive fashion. 7. The effects of 2-CA on synaptic transmission were abolished by pre-treatment with 250 ng/ml PTX, indicating that a PTX-sensitive G-protein is involved in this action. 8. These results indicate that activation of adenosine receptors does induce a reduction in ICa in hippocampal pyramidal neurones. Furthermore, this effect and the reduction of excitatory synaptic transmission by adenosine analogues are both mediated by PTX-sensitive G-proteins and have identical pharmacological properties.
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