Regulation of 5-HT(2A) receptor coupling and 5-HT(2A) receptor mRNA in P11 cells.

Format:

Book

Thesis/Dissertation

Author/Creator:

Wohlpart, Kathryn Louise.

Contributor:

University of Pennsylvania.

Language:

English

Subjects (All):

Pharmacology.

Cytology.

Molecular biology.

0307.

0379.

0419.

Local Subjects:

0307.

0379.

0419.

Physical Description:

126 pages

Contained In:

Dissertation Abstracts International 59-07B.

System Details:

Mode of access: World Wide Web.

text file

Summary:

Understanding mechanisms that regulate levels of 5-HT$\sb{\rm 2A}$ receptors and 5-HT$\sb{\rm 2A}$ receptor coupling has important implications in understanding processes involved in neurobiological disorders such as schizophrenia and depression. P11 cells, which express endogenous 5-HT$\sb{\rm 2A}$ receptors, have been used as a model system to investigate the regulation of 5-HT$\sb{\rm 2A}$ receptor mRNA and 5-HT$\sb{\rm 2A}$ receptor coupling to second messengers.

Multiple pathways exist in P11 cells that lead to increased levels of 5-HT$\sb{\rm 2A}$ receptor mRNA. Levels of 5-HT$\sb{\rm 2A}$ receptor mRNA are up-regulated in response to treatment with 5-HT, PMA or ionomycin due to an increase in the stability of receptor mRNA. The ability of bisindolylmaleimide, an inhibitor of PKC, or genistein, an inhibitor of tyrosine kinases, to completely inhibit 5-HT-, PMA- or ionomycin-induced increases in levels of receptor-mRNA, suggests that PKC and tyrosine kinase(s) are critical components of the pathways leading to increased levels of receptor mRNA. The ability of 5-HT, PMA and ionomycin to activate distinct isoforms of PKC suggests that multiple isoforms of PKC are linked to increases in levels of 5-HT$\sb{\rm 2A}$ receptor mRNA in P11 cells.

Coupling of 5-HT$\sb{\rm 2A}$ receptors to activation of second messenger pathways is also regulated by PKC. Although PKC does not appear to be involved in processes that mediate agonist-induced desensitization of 5-HT$\sb{\rm 2A}$ receptors, modification of 5-HT$\sb{\rm 2A}$ receptors by PKC in non-stimulated P11 cells appears to result in tonic inhibition of coupling of 5-HT$\sb{\rm 2A}$ receptors to second messenger pathways. Inhibition of PKC by bisindolylmaleimide results in a change in the conformational state of 5-HT$\sb{\rm 2A}$ receptors that results in increased efficacy of full agonists for coupling to stimulation of PI hydrolysis and the unmasking of a small, but significant amount of constitutive receptor activity.

Notes:

Source: Dissertation Abstracts International, Volume: 59-07, Section: B, page: 3369.

Supervisor: Perry B. Molinoff.

Thesis (Ph.D.)--University of Pennsylvania, 1998.

Local Notes:

School code: 0175.

ISBN:

9780591941401

Access Restriction:

Restricted for use by site license.