Comparative recovery kinetics of 5-hydroxytryptamine 1A, 1B, and 2A receptor subtypes in rat cortex after receptor inactivation: evidence for differences in receptor production and degradation
Pinto, W.; Battaglia, G.
Molecular Pharmacology 46(6): 1111-1119
1994
ISSN/ISBN: 0026-895X PMID: 7808431 Document Number: 427895
The present study investigates the comparative repopulation kinetics of 5-hydroxytryptamine (5-HT)-1A, 5-HT-1B, and 5-HT-2A receptors in rat cortex homogenates after irreversible receptor inactivation by N-ethoxycarbonyl-1,2-ethoxydihydroquinoline. Adult male rats were administered a single subcutaneous dose of vehicle (1:1 ethanol/water) or N-ethoxycarbonyl-1,2-ethoxydihydroquinoline (10 mg/kg), and the recovery of 5-HT receptor subtypes was measured at various times after injection (4-336 hr). Despite comparable control B-max values for 5-HT-1A (84 +- 2 fmol/mg of protein) and 5-HT-1B (94 +- 4 fmol/mg) subtypes, marked differences were noted in their 1) receptor production rates (r = 0.349 versus 0.235 fmol/mg of protein/hr), 2) receptor degradation rate constants (k = 0.0056 versus 0.0033 hr-1), and 3) half-lives of receptor recovery (1 24.1 versus 21 2.5 hr). For 5HT-2A receptors, both r and k for agonist ((+-)-1-(2,5-dimethoxy4-(125I)iodophenyl)-2-aminopropane)- or antagonist ((3H)ketanserin)-labeled sites were markedly greater than the respective values for the 5-HT, subtypes. In addition, the significantly different B-max values for agonist- versus antagonist-labeled 5-HT-2A receptors (79 +- 4 versus 206 +- 10 fmol/mg) were reflected exclusively as a 2.6-fold difference in receptor production rates, because degradation rate constants (k) were identical. Moreover, the stoichiometry of agonist-labeled to antagonist-labeled 5-HT-2A receptors was not altered at any time point during recovery. These data indicate that 1) comparable receptor steady state B-max values for 5-HT receptor subtypes may be due to markedly different receptor kinetic parameters (r and k), 2) differences in r and k are greater between 5-HT receptor families (i.e., 5-HT-1 versus 5-HT-2) than among subtypes within a family (i.e., 5-HT-1A versus 5-HT-1B), and, 3) despite marked changes in 5-HT-2A receptor density, the percentage of receptors in the agonist-labeled, high affinity state is maintained.