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Cane Toad Skin Extract—Induced Upregulation and Increased Interaction of Serotonin 2A and D 2 Receptors via G q/11 Signaling Pathway in CLU213 Cells
Author(s) -
Zulfiker Abu Hasanat Md.,
Hashimi Saeed M.,
Good David A.,
Grice I. Darren,
Wei Ming Q.
Publication year - 2017
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25627
Subject(s) - agonist , receptor , downregulation and upregulation , striatum , western blot , 5 ht receptor , chemistry , serotonin , transcription factor , signal transduction , pharmacology , microbiology and biotechnology , dopamine , medicine , neuroscience , biology , biochemistry , gene
Recent evidences show that activation of serotonin 2A receptors (5‐HT 2A R) by agonists is significant in improving therapeutic activity of disease conditions, such as obsessive‐compulsive disorder (OCD). Though the exact molecular mechanism is still not well understood, it is thought to involve agonist‐driven, enhanced expression of 5‐HT 2A R in certain areas of brain, such as the pre‐frontal cortex (PFC). Several other reports have also demonstrated association of OCD with lower dopamine receptor (D 2 R) availability, primarily in the striatum of the brain along with dysfunction of 5‐HT 2A R‐D 2 R heteromer regulation. We thus hypothesized that compound(s) interacting with this molecular mechanism could be developed as drugs for long‐term beneficial effects against OCD. In the present study, we have obtained experimental evidence in cultured neuronal cells (CLU213) that aqueous extract (AE, 50 μg/mL, P < 0.05) of the Australian cane toad skin significantly increased the levels of 5‐HT 2A R and D 2 R protein and mRNA expression. AE was also found to enhance the interaction between 5‐HT 2A R and D 2 R and formation of expression of 5‐HT 2A R‐D 2 R heteromer using co‐immunoprecipitation and Western blot. Further investigation showed the involvement of classical signaling pathway (G q/11 ‐PLCβ) along with c‐FOS transcription factor preferentially in 5‐HT 2A ‐mediated agonist activation. These results obtained demonstrated that AE upregulates 5‐HT 2A R by a mechanism that appears to involve G q/11 ‐PLCβ signaling pathway and c‐FOS transcription factor activation. We indicate this enhanced 5‐HT 2A R and D 2 R expression and their interaction to induce increased 5‐HT 2A R‐D 2 R heteromer formation by exposure to AE might provide a molecular mechanism to develop potential novel drug candidates to ameliorate OCD symptoms. J. Cell. Biochem. 118: 979–993, 2017. © 2016 Wiley Periodicals, Inc.