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Single amino acid mutations at 195 and 199 of the human glycine receptor beta subunit alter the sensitivity of the glycine receptor to agonist

, : Single amino acid mutations at 195 and 199 of the human glycine receptor beta subunit alter the sensitivity of the glycine receptor to agonist. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 797 2

Glycine is the major inhibitory transmitter in the spinal cord. Molecular cloning has identified two glycine receptor subunits,alpha and beta. These subunits are capable of forming a heteromeric complex with a stiochiometry thought to be 3alpha:2beta. Although previous mutagenesis studies of the glycine receptor identified discrete sites in the alpha subunit that alter agonist and antagonist sensitivity, little is known about the functional role of amino acids in the beta subunit. Based on recent molecular modeling of a molluscan acetylcholine-binding protein, we have identified two residues, glutamine (Q) at 195 and methionine (M) at 199, in the human glycine receptor beta subunit, which are located in the middle of a cys-cys loop and are adjacent to what is thought to be an agonist binding site. To evaluate the functional role of these beta subunit residues, we substituted Q195 with a lysine (K) or M199 with an arginine (R), co-expressed the wild-type or mutant beta subunit with the wild-type alpha subunit in Xenopus oocytes and studied the function of these receptors using two-electrode voltage-clamp. In cells expressing receptors with a mutant beta subunit, the maximal amplitude of current was not significantly different from the wild-type. However, both the Q195K and the M199R mutation shifted the glycine concentration-response curve to the right in a parallel manner and increased the EC50 value for glycine by apprx4-fold. This indicates that point mutations at Q195 or M199 of the beta subunit can alter the sensitivity of glycine receptor to agonist, suggesting that the beta subunit of the receptor may play an important role in the activation mechanism of the heteromeric glycine receptor.


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