Cane Toad Skin Extract-Induced Upregulation and Increased Interaction of Serotonin 2A and D2Receptors via Gq/11Signaling Pathway in CLU213 Cells.
Recent evidences show that activation of serotonin 2A receptors (5-HT2AR) 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-HT2AR 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 (D2R) availability, primarily in the striatum of the brain along with dysfunction of 5-HT2AR-D2R 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-HT2AR and D2R protein and mRNA expression. AE was also found to enhance the interaction between 5-HT2AR and D2R and formation of expression of 5-HT2AR-D2R heteromer using co-immunoprecipitation and Western blot. Further investigation showed the involvement of classical signaling pathway (Gq/11-PLCβ) along with c-FOS transcription factor preferentially in 5-HT2A-mediated agonist activation. These results obtained demonstrated that AE upregulates 5-HT2AR by a mechanism that appears to involve Gq/11-PLCβ signaling pathway and c-FOS transcription factor activation. We indicate this enhanced 5-HT2AR and D2R expression and their interaction to induce increased 5-HT2AR-D2R 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.
School of Medical Science and Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.
Abu Hasanat Md
AH
Zulfiker
School of Medical Science and Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.|Department of Biology, Deanship of Preparatory Year, University of Dammam, Dammam, Kingdom of Saudi Arabia.
Saeed M
SM
Hashimi
School of Medical Science and Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.|School of Physiotherapy, Banyo Campus, Australian Catholic University, Queensland, 4014, Australia.
David A
DA
Good
Institute for Glycomics and School of Medical Science, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.
I Darren
ID
Grice
School of Medical Science and Menzies Health Institute Queensland, Gold Coast Campus, Griffith University, Queensland, 4222, Australia.
Ming Q
MQ
Wei
D000818:Animals; D001001:Anura / Q000378:metabolism*; D002460:Cell Line; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000737:chemistry*; D014020:Tissue Extracts / Q000494:pharmacology*; D015533:Transcriptional Activation; D015854:Up-Regulation
D016760:Proto-Oncogene Proteins c-fos; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D014020:Tissue Extracts; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
AQUEOUS EXTRACT; AUSTRALIAN CANE TOAD SKIN; CLU213 CELLS; Gq/11; SIGNALING PATHWAY