Vol. 301, Issue 2, 765-773, May 2002

Enhanced Inhibition of a Mutant Neuronal Nicotinic Acetylcholine Receptor by Agonists: Protection of Function by (E)-N-Methyl-4-(3-pyridinyl)-3-butene-1-amine (TC-2403)

Roger L. Papke

Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida

Inhibition of neuronal nicotinic receptors can be regulated by sequence in the  subunit second transmembrane domain (TM2). The incorporation of a 4(6'F10'T) subunit, which contains sequence from the muscle  subunit at the TM2 6' and 10' positions of the neuronal 4 subunit, increases the loss of receptor responsiveness after the application of acetylcholine (ACh), nicotine, or 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB), an 7-selective partial agonist. Inhibition of receptor responsiveness following agonist exposure may occur through either an enhancement of desensitization, increased channel block by an agonist, or alternatively via allosteric modulation. Although DMXB produces very little activation of either 34 or 34(6'F10'T) receptors, DMXB shows an enhanced use-and voltage-dependent inhibition of 34(6'F10'T) receptors compared with wild-type. In contrast, the 42-selective agonist (E)-N-methyl-4-(3-pyridinyl)-3-butene-1-amine (TC-2403, previously identified as RJR-2403) shows increased activation of 34(6'F10'T) receptors compared with 34 receptors (as related to ACh activation) but with no significant increase in antagonist activity. The interaction between the binding of local anesthetics and the functional inhibition produced by these agonists was evaluated. The binding of the local anesthetics to their inhibitory sites does not affect inhibitory effects of DMXB and nicotine. However, TC-2403 can protect receptor function from the inhibitory effects of other agonists, suggesting that TC-2403, as well as agonists that cause inhibition, may be binding to an allosteric site, either promoting or inhibiting channel opening. The ability of TC-2403 to protect receptor function from agonist-induced inhibition may point toward valuable new combination drug therapies.