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J Akiyoshi, C Hough and DM Chuang
Section on Molecular Neurobiology, National Institute of Mental Health, Bethesda, Maryland 20892.
Rat cerebellar granule cells express 5-hydroxytryptamine (5-HT)2 receptors that mediate phosphoinositide turnover by a pertussis toxin- sensitive mechanism. Prestimulation of these neurons with 10 microM 5- HT or (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane [(+/-)-DOI], a putative 5-HT2 receptor agonist, resulted in a time-dependent desensitization of the phosphoinositide response to 5-HT. The desensitization was detected within 30 min after prestimulation and reached a maximum (about 80%) decrement at 8 hr. However, [3H]ketanserin binding to 5-HT2 receptors in crude membranes or intact cerebellar granule cells was increased by treatment with 5-HT or DOI, in a time- and concentration-dependent manner. The increase occurred after the onset of desensitization and was fully manifest (about 160- 190%) at 4 hr after stimulation. Although the Bmax and Kd were unchanged at 1 hr after 5-HT or DOI treatment, both parameters were significantly increased at 4 and 24 hr. The amount of 5-HT2 receptor mRNA detected by Northern blot hybridization using a 5-HT2 receptor- specific riboprobe was increased in parallel with the up-regulation of 5-HT2 receptor binding sites. Thus, an increase in 5-HT2 receptor mRNA was detected within 2 hr after 5-HT or DOI prestimulation, reached a maximum around 4 hr, and remained at a plateau for at least 24 hr. The levels of total RNA, m3 muscarinic acetylcholine receptor mRNA, and beta-actin mRNA were not significantly affected by these treatments. Our results demonstrated that 5-HT2 receptor binding sites and their mRNA undergo a paradoxical induction during persistent agonist stimulation.
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