G protein-coupled receptors for dopamine and serotonin control signaling pathways targeted by many psychoactive drugs. A puzzle is how receptors with similar functions and nearly identical binding site structures, such as D2 dopamine receptors and 5-HT2A serotonin receptors, could evolve a mechanism that discriminates stringently in their cellular responses between endogenous neurotransmitters. We used the Difference Evolutionary Trace (Difference-ET) and residue-swapping to uncover two distinct sets of specificity-determining sequence positions. One at the ligand-binding pocket determines the relative affinities for these two ligands, and a distinct, surprising set of positions outside the binding site determines whether a bound ligand can trigger the conformational rearrangement leading to G protein activation. Thus one site specifies affinity while the other encodes a filter for efficacy. These findings demonstrate that allosteric pathways linking distant interactions via alternate conformational states enforce specificity independently of the ligand-binding site, such that either one may be rationally rekeyed to different ligands. The conversion of a dopamine receptor effectively into a serotonin receptor illustrates the plasticity of GPCR signaling during evolution, or in pathological states, and suggests new approaches to drug discovery, targeting both classes of sites.

Objective To determine the predictive value of discharge destination as a surrogate for defining unfavorable outcome at 3- and 12-months poststroke. Design Analysis of the prospectively collected data from a randomized, placebo-controlled trial in patients with ischemic stroke presenting within 3 hours of symptom onset. Setting Post hoc analysis of patients recruited in a clinical trial. Participants Patients (N=530) discharged alive from the hospital after ischemic stroke. Interventions Not applicable. Main Outcome Measures Positive and negative predictive value and likelihood ratios of discharge destination for unfavorable outcome at 3- and 12-months poststroke defined by a Modified Rankin Scale (MRS) score of 2 to 6, 3 to 6, or 4 to 6. A likelihood ratio indicates how many times more (or less) likely a particular discharge destination is seen in patients with an unfavorable outcome compared with those without unfavorable outcome. Results The positive predictive value of nursing home and rehabilitation facility discharges was highest for unfavorable outcome defined by an MRS score of 2 to 6 (95%) and rehabilitation facility (89%) at 3-months poststroke, respectively. The positive predictive value of rehabilitation facility/nursing home (90%) was also highest for unfavorable outcomes defined by an MRS score of 2 to 6 compared with those defined by MRS scores of 3 to 6 (79%) and 4 to 6 (57%). The positive likelihood ratio was highest for nursing home discharges (13; 95% confidence interval [CI], 4.1– 41) followed by rehabilitation facility discharges for unfavorable outcome defined by an MRS score of 2 to 6 at 3-months poststroke (5.3; 95% CI, 3.5–7.9). The negative likelihood ratio was the highest for home discharge for unfavorable outcome defined by an MRS score of 2 to 6 (4.5; 95% CI, 3.4 – 6.1). A similar pattern was observed with unfavorable outcome defined using various thresholds at 12 months. Conclusions Discharge destination can provide high predictive values and likelihood ratios for death and disability at 3-months poststroke, as defined by an MRS of score of 2 to 6.

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