The Journal of Neuroscience, February 15, 2002, 22(4):1248-1255
Differential Desensitization of Responses Mediated by Presynaptic
and Postsynaptic A1 Adenosine Receptors
Jonathon P.
Wetherington and
Nevin
A.
Lambert
Department of Pharmacology and Toxicology, Medical College of
Georgia, and Medical Research Service, Augusta Veterans Affairs Medical
Center, Augusta, Georgia 30912
G-protein-coupled receptors (GPCRs) often desensitize during
continuous activation, but it is not known whether desensitization is
influenced by subcellular location. In hippocampal neurons, activation
of adenosine A1 receptors (A1Rs) or GABAB
receptors on synaptic terminals inhibits neurotransmitter release,
whereas activation of the same receptors on cell bodies and dendrites decreases excitability by activating inwardly rectifying potassium (GIRK) channels. Here we report that responses mediated by presynaptic A1Rs desensitize more slowly than responses mediated by postsynaptic (somatodendritic) A1Rs in cultured neurons. Agonist treatment for 2 hr
has no effect on adenosine-induced presynaptic inhibition, whereas such
treatment nearly abolishes adenosine-induced activation of postsynaptic
GIRK channels. Agonist treatment for longer periods (>12 hr)
eventually desensitizes A1R-mediated presynaptic inhibition. Presynaptic and postsynaptic responses both recover from
desensitization after agonist removal, but recovery of presynaptic
inhibition requires more time. Desensitization of postsynaptic
responses apparently occurs at the level of the receptor, because
postsynaptic G-proteins and GIRK channels appear to be fully
functional. Inhibition of voltage-gated calcium channels by
postsynaptic A1Rs also desensitizes rapidly, although this
desensitization is less complete than is observed for activation of
postsynaptic GIRK channels. Comparison of concentration-response
curves for presynaptic and postsynaptic responses suggests that a
receptor reserve exists for presynaptic inhibition, but that the
magnitude of this reserve is insufficient to account for the absence of
presynaptic desensitization after brief agonist exposure. These results
suggest that agonist-induced desensitization of responses mediated by
neuronal GPCRs may depend on the subcellular location of the receptors.
Key words:
desensitization; downregulation; GPCR; presynaptic
inhibition; GIRK; adenosine; GABAB
Copyright © 2002 Society for Neuroscience 0270-6474/02/2241248-08$05.00/0
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