The beta subunit of neuronal nicotinic acetylcholine receptors is a determinant of the affinity for substance P inhibition.
Substance P is known to inhibit nicotinic acetylcholine receptors from neuronal tissue, skeletal muscle, and electroplaque. The interaction of substance P with specific combinations of neuronal nicotinic acetylcholine receptor subunits was studied by expressing various combinations of subunits in Xenopus oocytes. The response to acetylcholine was inhibited by substance P with all subunit combinations tested; however, the apparent affinity for substance P varied by 20-30-fold. The affinity seemed to be dependent on the beta subtype expressed (beta 4 or beta 2). This suggests that the beta subunit may contribute, at least partially, to the substance P binding site. In the case of the alpha 7 subtype, which forms a homooligomeric receptor, the apparent affinity for substance P was intermediate between those of the two beta subtypes coexpressed with either alpha 3 or alpha 4. As previously found, the inhibition was noncompetitive. Furthermore, the inhibition was not voltage dependent and, therefore, is unlikely to be due to substance P blocking the channel within the transmembrane portion of the pore.
Stafford
G A
GA
Department of Pharmacology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853.
Oswald
R E
RE
Weiland
G A
GA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins; D013329:Structure-Activity Relationship; D013373:Substance P / Q000494:pharmacology*; D014982:Xenopus laevis
D011978:Receptors, Nicotinic; D011994:Recombinant Proteins; D013373:Substance P; D000109:Acetylcholine