Evidence for a multi-site model of the rat brain sigma receptor.
Irradiation of rat brain membranes with light of 254 nm, a treatment which modifies ultra-violet absorbing residues in proteins, decreased binding of both [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ([ 3H](+)-3-PPP) and [3H]1,3-di-o-tolylguanidine ([3H]DTG) to sigma receptors. For [3H](+)-3-PPP, this was due to a decreased Bmax. In contrast, irradiation markedly increased binding of [3H](+)-N-allylnormetazocine ([3H](+)-SKF 10,047) due to a decrease in the Kd. Both unlabeled DTG and haloperidol were competitive inhibitors of [3H](+)-3-PPP binding to untreated membranes, causing an increase in the Kd and no change in the Bmax. The benzomorphans, (+)-SKF 10,047 and (+)-pentazocine, were uncompetitive inhibitors, causing a decrease in both the Kd and Bmax for [3H](+)-3-PPP. Finally, the ability of DTG and (+)-3-PPP to inhibit binding of [3H](+)-SKF 10,047 was markedly reduced by ultra-violet irradiation, whereas irradiation had little effect on the potency of unlabeled (+)-SKF 10,047 and (+)-pentazocine. These data suggest that sigma-related (+)-benzomorphans and non-benzomorphans interact either with distinct, allosterically coupled sites on the same sigma receptor macromolecule or with different populations of sigma receptor types.
Bowen
W D
WD
Division of Biology and Medicine, Brown University, Providence, RI 02912.
Hellewell
S B
SB
McGarry
K A
KA
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000528:radiation effects; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism / Q000528:radiation effects; D008954:Models, Biological; D010620:Phenazocine / Q000031:analogs & derivatives / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D013574:Synaptosomes / Q000378:metabolism / Q000528:radiation effects; D014466:Ultraviolet Rays
D010880:Piperidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; C012134:SK&F 10047; C026539:preclamol; D010620:Phenazocine