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Vol. 57, Issue 6, 1114-1122, June 2000
Divisions of Biology (H.D., S.S.F., H.A.L.) and Chemistry
and Chemical Engineering (P.M.E., D.A.D.), California Institute of
Technology, Pasadena, California
A conserved proline residue is found in the first transmembrane domain
(M1) of every subunit in the ligand-gated ion channel superfamily. The
position of this proline between the N-terminal extracellular agonist
binding and the second transmembrane (M2) channel lining domains in the
primary sequence suggests its possible involvement in the gating of the
receptor. Replacing this proline with alanine, glycine, or leucine in
the 5-hydroxytryptamine (5-HT)3A homomeric receptors
expressed in Xenopus laevis oocytes resulted in the
absence of 5-HT-induced whole-cell currents, although there were normal
levels of specific surface [3H]granisetron
([3H]BRL-43694) binding sites. To determine what
properties of the conserved proline are critical for the function of
the channel, two imino acids and an 
-hydroxy acid were incorporated
at the proline position using the nonsense suppression method.
trans-3-Methyl-proline, pipecolic acid, and leucic acid
were able to replace the conserved proline to produce active channels
with EC50 values similar to that for the wild-type
receptor. These trends are preserved in the heteromeric receptors
consisting of 5-HT3A and 5-HT3B subunits in
oocytes. The prominent common feature among these residues and proline
is the lack of hydrogen bond donor activity, potentially resulting in a
flexible secondary structure in the M1 region. Thus, lack of hydrogen
bond donor activity may be a key element in channel gating and may
explain the high degree of conservation of this M1 proline.
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