Protein coalitions in a core mammalian biochemical network linked by rapidly evolving proteins

<p>Abstract</p> <p>Background</p> <p>Cellular ATP levels are generated by glucose-stimulated mitochondrial metabolism and determine metabolic responses, such as glucose-stimulated insulin secretion (GSIS) from the β-cells of pancreatic islets. We describe an analysis of the evolutionary processes affecting the core enzymes involved in glucose-stimulated insulin secretion in mammals. The proteins involved in this system belong to ancient enzymatic pathways: glycolysis, the TCA cycle and oxidative phosphorylation.</p> <p>Results</p> <p>We identify two sets of proteins, or protein coalitions, in this group of 77 enzymes with distinct evolutionary patterns. Members of the glycolysis, TCA cycle, metabolite transport, pyruvate and NADH shuttles have low rates of protein sequence evolution, as inferred from a human-mouse comparison, and relatively high rates of evolutionary gene duplication. Respiratory chain and glutathione pathway proteins evolve faster, exhibiting lower rates of gene duplication. A small number of proteins in the system evolve significantly faster than co-pathway members and may serve as rapidly evolving adapters, linking groups of co-evolving genes.</p> <p>Conclusions</p> <p>Our results provide insights into the evolution of the involved proteins. We find evidence for two coalitions of proteins and the role of co-adaptation in protein evolution is identified and could be used in future research within a functional context.</p

Genetic Variation of the Serotonin 2a Receptor Affects Hippocampal Novelty Processing in Humans

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing

Variation in dopamine D2 and serotonin 5-HT2A receptor genes is associated with working memory processing and response to treatment with antipsychotics

Dopamine D2 and serotonin 5-HT2A receptors contribute to modulate prefrontal cortical physiology and response to treatment with antipsychotics in schizophrenia. Similarly, functional variation in the genes encoding these receptors is also associated with these phenotypes. In particular, the DRD2 rs1076560 T allele predicts a lower ratio of expression of D2 short/long isoforms, suboptimal working memory processing, and better response to antipsychotic treatment compared with the G allele. Furthermore, the HTR2A T allele is associated with lower 5-HT2A expression, impaired working memory processing, and poorer response to antipsychotics compared with the C allele. Here, we investigated in healthy subjects whether these functional polymorphisms have a combined effect on prefrontal cortical physiology and related cognitive behavior linked to schizophrenia as well as on response to treatment with secondgeneration antipsychotics in patients with schizophrenia. In a total sample of 620 healthy subjects, we found that subjects with the rs1076560 T and rs6314 T alleles have greater fMRI prefrontal activity during working memory. Similar results were obtained within the attentional domain. Also, the concomitant presence of the rs1076560 T/rs6314 T alleles also predicted lower behavioral accuracy during working memory. Moreover, we found that rs1076560 T carrier/rs6314 CC individuals had better responses to antipsychotic treatment in two independent samples of patients with schizophrenia (n¼63 and n¼54, respectively), consistent with the previously reported separate effects of these genotypes. These results indicate that DRD2 and HTR2A genetic variants together modulate physiological prefrontal efficiency during working memory and also modulate the response to antipsychotics. Therefore, these results suggest that further exploration is needed to better understand the clinical consequences of these genotype–phenotype relationships