Oxotremorine-M stimulated [35S]GTP gamma S binding was used to assess acetylcholine muscarinic M2 receptor mediated G-protein function in superior frontal cortical, superior temporal cortical and hippocampal membranes from a series of Alzheimer's disease and matched control subjects. No significant differences were seen in basal [35S]GTP gamma S binding between the groups. The maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was significantly increased in Alzheimer's disease superior temporal cortex, suggesting an enhanced muscarinic M2 receptor-G-protein coupling efficiency in this region. In contrast, the maximal level of oxotremorine-M stimulated [35S]GTP gamma S binding over basal was unaltered in Alzheimer's disease superior frontal cortex and significantly reduced in Alzheimer's disease hippocampus. Western immunoblotting using antisera towards the alpha-subunits of those G-protein types known to couple muscarinic receptors, revealed that Gq alpha and Gi alpha, but not G(o) alpha, levels were significantly reduced in Alzheimer's disease superior temporal cortex. Neither Gq alpha, Gi alpha, nor G(o) alpha levels were significantly altered in Alzheimer's disease superior frontal cortex or hippocampus. These results suggest that the efficacy of muscarinic M2 receptor G-protein coupling shows regional selective changes in Alzheimer's disease postmortem brain with deficits occurring only in a region that shows severe pathology.