An arginyl in the N-terminus of the V1a vasopressin receptor is part of the conformational switch controlling activation by agonist.

Defining how the agonist-receptor interaction differs from that of the antagonist-receptor and understanding the mechanisms of receptor activation are fundamental issues in cell signalling. The V1a vasopressin receptor (V1aR) is a member of a family of related G-protein coupled receptors that are activated by neurohypophysial peptide hormones, including vasopressin (AVP). It has recently been reported that an arginyl in the distal N-terminus of the V1aR is critical for binding agonists but not antagonists. To determine specific features required at this locus to support high affinity agonist binding and second messenger generation, Arg46 was substituted by all other 19 encoded amino acids. Our data establish that there is an absolute requirement for arginyl, as none of the [R46X]V1aR mutant constructs supported high affinity agonist binding and all 19 had defective signalling. In contrast, all of the mutant receptors possessed wildtype binding for both peptide and nonpeptide antagonists. The ratio of Ki to EC50, an indicator of efficacy, was increased for all substitutions. Consequently, although [R46X]V1aR constructs have a lower affinity for agonist, once AVP has bound all 19 are more likely than the wildtype V1aR to become activated. Therefore, in the wildtype V1aR, Arg46 constrains the inactive conformation of the receptor. On binding AVP this constraint is alleviated, promoting the transition to active V1aR. Our findings explain why arginyl is conserved at this locus throughout the evolutionary lineage of the neurohypophysial peptide hormone receptor family of G-protein coupled receptors.

Planning an overseas extension programme

An educational program in another country establishes the mechanism for a variety of other possibilities. Faculty in the host country may provide the setting in which U.S. students can gain interculteral experience. Students may be able to conduct an independent study in the host or, if sufficient numbers are available, a U.S. course may be adapted and offered in the host country. If ample funds exist, a two-way student and/or faculty exchange may be possible, thereby adding to the curricula of both schools. Opportunities for joint research and publishing may also become available. For example, long term evaluation of the educational program and use of the program graduates in the host country would be of interest; research in the specialty areas of faculty may also be possible. The difficulties inherent in planning and implementing a program in another country are numerous; however, with foresight and ample time for planning, the benefits to both students and faculty in the host and home institutions can outweigh the drawbacks (AU)