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Vol. 59, Issue 4, 844-851, April 2001
-Homomeric 5-Hydroxytryptamine Type 3 Receptors
Department of Cell Physiology, Ruhr-University Bochum,
Universitätsstrasse 150, 44780 Bochum, Germany
Desensitization of ligand-gated ion channels shapes synaptic responses
and provides critical neuroprotection at central synapses, yet the
molecular mechanisms underlying the desensitization process are poorly
understood. Using the whole-cell voltage-clamp technique, we
investigated desensitization kinetics of recombinant human and guinea
pig 
-homomeric 5-hydroxytryptamine type 3 (5-HT3A) receptors heterologously expressed in human embryonic kidney 293 cells.
Human 5-HT3A receptors desensitize 3.5 times faster than does the homologous receptor from guinea pigs. By constructing various
chimeras and through site-directed mutagenesis, we have identified a
single serine in the M1 region of the human 5-HT3A receptor
sequence (S248) that, when substituted with threonine found in the
equivalent guinea pig sequence (T254), conferred guinea pig-like
kinetics on the time course of desensitization of the human receptor.
Correspondingly, the reverse mutation (guinea pig T254S) resulted in a
fast, human-like time constant of desensitization. Thus, the primary
structure of the M1 region is an important determinant of
desensitization kinetics of recombinant 5-HT3A receptors.
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