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5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation
B L Roth1, E P Palvimaki, S Berry
1Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
The Journal of Pharmacology and Experimental Therapeutics
|December 1, 1995
Summary
Agonist exposure desensitizes serotonin 5-HT2A receptors without changing receptor number. Protein kinase C isozymes mediate early desensitization, but later stages occur independently of these enzymes.
Area of Science:
- Pharmacology
- Cell Biology
- Neuroscience
Background:
- Serotonin 5-HT2A receptors are crucial for neurotransmission.
- Agonist-induced desensitization affects receptor function.
- Understanding desensitization mechanisms is key for therapeutic development.
Purpose of the Study:
- To investigate the mechanisms of agonist-induced desensitization and down-regulation of 5-HT2A receptors.
- To determine the role of G proteins and protein kinase C (PKC) in 5-HT2A receptor desensitization.
Main Methods:
- Utilized a clonal cell line stably expressing 5-HT2A receptors.
- Employed agonist exposure (quipazine, DOI) for varying durations.
- Conducted phosphoinositide hydrolysis assays, immunohistochemistry, Western blot analysis, and studies with mutant receptors and PKC isozymes.
Main Results:
- Agonist exposure (2-24 hr) reduced 5-HT2A receptor-mediated phosphoinositide hydrolysis without altering receptor number or affinity.
- Prolonged agonist exposure did not affect surface receptor immunoreactivity or phospholipase C-coupled G protein levels.
- Down-regulation of PKC isozymes alpha and epsilon attenuated the intermediate phase of desensitization, but not the later phase.
Conclusions:
- 5-HT2A receptor desensitization can occur independently of G protein levels.
- The intermediate phase of desensitization involves PKC alpha and/or epsilon isozymes.
- Later-phase desensitization mechanisms are independent of PKC and G protein levels.