The 5HTla receptor (R) has been implicated in a number of neurochemical and behavioral phenomena. As a member of the superfamily of G-protein coupled, seven transmembrane receptors, knowledge of 5HTlaR biochemistry and pharmacology represents critical information, not only for the serotonin receptors, but for related neurotransmitter receptors such as the beta adrenergic and dopamine receptors. One especially fruitful area of research has involved expanding views of the interfacial surface between receptor and G protein. Progress in characterization of this receptor has been made in a number of laboratories worldwide, to the extent that specific hypotheses regarding receptor-G protein relationships are now testable. We have developed a panel of short peptides based on the native sequence of the receptor`s transmembrane (TM) 5/intracellular (ic) loop 3 region. Data will be presented regarding the differential uncoupling and G protein activating properties of these peptides. Additionally, a limited number of peptides fiom the receptor`s TM3/ic2 loop region and from the C-terminus have been characterized. Our data in conjunction with information from other laboratories suggest roles for ic2 and ic3 in the biology of these receptors. As further probes of the 5HTlaR/G protein interface, projected studies with prototypical peptides selected from current work will utilize high resolution spectral techniques to refine structural models.