McIntire, William E.
Assistant Professor of Research, Molecular Physiology and Biological Physics
- PhD, University of South Carolina
PO Box 800886
320 Snyder Bldg., Fontaine Research Park
Charlottesville, VA 22908
Molecular determinants involved in the selective activation of BG dimers upon stimulation of a given receptor
Sequence variation in seven transmembrane spanning receptors, which couple to heterotrimeric G proteins, provides specificity for agonist recognition as well as activation of particular G proteins. A G protein is composed of an a subunit, and a b and a g subunit, which exist as a functional dimer; all three of these subunits are required for transfer of information from receptor to G protein. Each subunit is a member of a larger family of isoforms, distinguished by differences in both primary sequence and covalent modification. Signaling specificity between particular receptors and a and g subunit isoforms has been thoroughly studied, and both appear to contribute to the specificity of receptor:G protein interactions. In contrast, the interactions between receptor and the various b subunit isoforms are poorly understood. Reconstitution experiments from this laboratory have recently demonstrated that bg dimers containing the b1 isoform are notably poor in coupling G proteins to the adenosine A2a receptor when compared to dimers containing other b isoforms, such as b4. Interestingly, the adenosine A1 receptor does not appear to discriminate between the b1 and b4 isoforms. The goal of my research is to understand the molecular determinants involved in the selective activation of bg dimers upon stimulation of a given receptor. The adenosine A1 and A2a receptors will be used to create chimeric proteins, which will allow functional analysis of the various domains of each receptor. A parallel strategy will be used to compare the different domains of the b1 and b4 subunits. Defined sequence motifs on either receptor or the b subunit that influence signaling specificity will provide useful targets for pharmacological intervention.