The human 5-hydroxytryptamine 1A receptor differentially modulates phospholipase c and adenylyl cyclase activities |
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| Affiliation: | 1. Department of Biochemistry, University of Montreal, B.P. 6128, Succ. Centre ville, Montreal, Quebec H3C 3J7, Canada;2. Department of Pharmacology, University of Montreal, B.P. 6128, Succ. Centre ville, Montreal, Quebec H3C 3J7, Canada;1. Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Brig S. K. Mazumdar Marg, Delhi 110054, India;2. Department of Chemistry, Indian Institute of Technology, Delhi, Hauz-Khas, New Delhi 110016, India;3. Department of Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, Uttar Pradesh, India;1. Division of Radiological, Nuclear and Imaging Sciences, Institute of Nuclear Medicine and Allied Sciences, Brig S K Mazumdar Road, Timarpur, Delhi 110054, India;2. Department of Chemistry, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, Uttar Pradesh, India;3. Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India;4. Department of Chemistry, Shivaji College, University of Delhi, Delhi 110027, India;1. Protection and Decontamination Research Group, Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences, Delhi 110054, India;2. Nucleic Acid Research Lab, Department of Chemistry, University of Delhi, Delhi 110007, India;3. Department of Chemistry, Miranda House, University of Delhi, Delhi 110007, India |
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| Abstract: | In this study, we quantitate and compare the ability of the 5-hydroxytryptamine 1A (5-HTIA) receptor to modulate the activities of phospholipase C and adenylyl cyclase as a function of receptor concentration. We used a single clonal cell line permanently expressing the human 5-HTIA receptor, and progressively depleted the receptor concentration using an alkylating antagonist (N8-bromoacetyl-N1-3′-(4-indolyloxy)-2′-hydroxypropyl-Z-1,8-diamino-p-menthane, (±) Pindobind). For serotonin-induced phospholipase C stimulation, reductions in receptor number result in dose-response curves that shift downward and rightward, reflecting both a decreasing maximal effect as well as an increasing ED50. In contrast, depletion of more than 95% of the receptors has no effect on the maximal inhibition of forskolin-stimulated adenylyl cyclase activity. Moreover, at all receptor concentrations, the amount of serotonin required to produce half-maximal phospholipase C stimulation is several-fold more than that required to produce half-maximal inhibition of adenylyl cyclase activity. We conclude that the 5-HT1A receptor modulates these two pathways differently, and that the overall response to challenge with serotonin, in terms of both phosphatidyl inositol hydrolysis and cyclic AMP production, is dependent upon receptor number. |
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