We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A cytoplasmic region determines single-channel conductance in 5-HT<sub>3</sub> receptors.
- Authors
Kelley, Stephen P.; Dunlop, James I.; Kirkness, Ewen F.; Lambert, Jeremy J.; Peters, John A.
- Abstract
5-Hydroxytryptamine type 3 (5-HT[sub 3]) receptors are cation-selective transmitter-gated ion channels of the Cys-loop superfamily. The single-channel conductance of human recombinant 5-HT[sub 3] receptors assembled as homomers of 5-HT[sub 3A] subunits, or heteromers of 5-HT[sub 3A] and 5-HT[sub 3B] subunits, are markedly different, being 0.4 pS (refs 6, 9) and 16 pS (ref. 7), respectively. Paradoxically, the channel-lining M2 domain of the 5-HT[sub 3A] subunit would be predicted to promote cation conduction, whereas that of the 5-HT[sub 3B] subunit would not. Here we describe a determinant of single-channel conductance that can explain these observations. By constructing chimaeric 5-HT[sub 3A] and 5-HT[sub 3B] subunits we identified a region (the 'HA-stretch')[sup 10] within the large cytoplasmic loop of the receptor that markedly influences channel conductance. Replacement of three arginine residues unique to the HA-stretch of the 5-HT[sub 3A] subunit by their 5-HT[sub 3B] subunit counterparts increased single-channel conductance 28-fold. Significantly, ultrastructural studies of the Torpedo nicotinic acetylcholine receptor indicate that the key residues might frame narrow openings that contribute to the permeation pathway. Our findings solve the conundrum of the anomalously low conductance of homomeric 5-HT[sub 3A] receptors and indicate an important function for the HA-stretch in Cys-loop transmitter-gated ion channels.
- Publication
Nature, 2003, Vol 424, Issue 6946, p321
- ISSN
0028-0836
- Publication type
Academic Journal
- DOI
10.1038/nature01788