Kinetic analysis of thyrotropin-releasing hormone binding in the central nervous system: evidence for receptor desensitization.
To investigate the mechanism(s) of experimentally and clinically observed refractoriness of spinal lower motor neurons (LMNs) to the excitatory effects of high-dose TRH, we examined the kinetics of dissociation of [3H]TRH from its CNS-receptor. At 23 degrees C, the receptor was rapidly (40 min) and completely converted from a form with fast dissociation kinetics (complex I; t1/2 20-30 min) to one from which the peptide dissociated much more slowly (complex II; t1/2 greater than 120 min). This conversion required the presence of added agonist ([3H]TRH) and was not prevented by the GTP-analog Gpp(NH)p. We suggest that complexes I and II may respectively represent active and inactive (desensitized) forms of the TRH-receptor and that TRH-induced I to II conversion of the receptor is responsible for refractoriness of LMNs to the drug.
Hawkins
E F
EF
USC Neuromuscular Center, Los Angeles 90017.
Engel
W K
WK
D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001414:Bacitracin; D002540:Cerebral Cortex / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D018025:Receptors, Thyrotropin-Releasing Hormone; D013347:Subcellular Fractions / Q000378:metabolism; D013696:Temperature; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*
D006150:Guanine Nucleotides; D017981:Receptors, Neurotransmitter; D018025:Receptors, Thyrotropin-Releasing Hormone; D001414:Bacitracin; D013973:Thyrotropin-Releasing Hormone