Abstract
Long-term exposure to nicotinic ligands results in up-regulation of neuronal nicotinic α4β2 receptors in the brain and in heterologous expression systems. Up-regulation can be produced by a variety of drugs, including nicotinic agonists and competitive antagonists, but previous studies have indicated that the signal for up-regulation does not reflect a traditional nicotinic pharmacology, and the initial steps in signal transduction are not clear. We examined the signal for up-regulation and the possible involvement of the nicotine binding site in signal reception using mutated subunits transiently expressed in human embryonic kidney 293 cells. The data indicate that receptor activation and desensitization are not part of the signaling pathway. However, mutations to residues in the binding site can affect up-regulation. These results provide evidence that the binding site is directly involved in receiving the signal for up-regulation.
Footnotes
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This research was supported by National Institutes of Health NS 22356. J.H.S. is the Russell and Mary Shelden Professor of Anesthesiology.
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ABBREVIATIONS: dHbE, dihydro-β-erythroidine; HEK, human embryonic kidney; ELISA, enzyme-linked immunosorbent assay; PBS, phosphatebuffered saline; mAb, monoclonal antibody; WT, wild type; N.S., not significant.
- Received July 25, 2006.
- Accepted September 11, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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