Identification of an epitope in the substance P receptor important for recognition of the common carboxyl-terminal tachykinin sequence.

The substance P receptor and the anti-substance P antibody NC1 share the ability to bind to the COOH terminus of substance P. Sequence analysis identified a direct noninterrupted homology of 5 residues in the two molecules. Replacement of Gly166 and Tyr167 in this epitope of the substance P receptor by the corresponding substance K receptor amino acids (Cys and Phe) increases the affinity toward substance P 2-fold and toward substance K and neurokinin B 11- and 21-fold, respectively. A significantly larger effect of the mutation is observed for the hexapeptides of substance P and substance K which show a mutation-induced increase in binding energy of more than 2 kcal/mol. Hence, the NH2 terminus of substance P and, to a lesser extent, of substance K masks the effect of the mutation. I conclude that the epitope is important for recognition of the common COOH terminus of the tachykinins and for preservation of selectivity. The data furthermore suggest that formation of the peptide-receptor complex occurs through a composite set of interactions which are not adequately described by the two-site/no cooperativity "address-message" model

A Mutation Changes Ligand Selectivity and Transmembrane Signaling Preference of the Neurokinin-1 Receptor

Abstract We studied the biochemical properties of a genetically engineered neurokinin-1 receptor (NK1R) in which two residues lying on the extracellular edge of the fourth transmembrane domain were replaced by equivalently located elements of the neurokinin-2 receptor (G166C, Y167F NK1R mutant). The mutation produced two effects. The first is enhancement of the apparent binding affinity for heterologous tachykinins (substance K and neurokinin B) and for N- or C-terminal modified analogues of substance P, but not for substance P itself, its full-length analogues, and several peptide and nonpeptide antagonists. Only two antagonists, as exceptions, were found to exhibit a diminished affinity for the mutant receptor. The second effect is a shift in NK1R preference for distinct G protein-mediated signaling pathways. NK1R-mediated phosphoinositide hydrolysis was enhanced both in transiently and permanently transfected cells, while stimulation of cAMP accumulation did not change in transient expression experiments and was reduced in permanently expressing cells. The effect of the mutation on ligand affinity was not related to any obvious structural commonality, nor to the selectivity for different neurokinin receptors or the agonistic/antagonistic nature of the ligand. However, all ligands responding to the mutation appear to share the ability to induce phosphoinositide signaling more efficiently than cAMP responses when binding to NK1R. We suggest that the mutation shifts the internal equilibria of different functional forms of NK1R. A theoretical analysis according to a multistate allosteric model suggests that the link between binding and biological changes can result from altered stability constants of substates in the conformational space of the receptor

Is an Early Age at Illness Onset in Schizophrenia Associated With Increased Genetic Susceptibility?

Background: Early age at illness onset has been viewed as an important liability marker for schizophrenia, which may be associated with an increased genetic vulnerability. A twin approach can be valuable, because it allows for the investigation of specific illness markers in individuals with a shared genetic background. Methods: We linked nationwide registers to identify a cohort of twin pairs born in Denmark from 1951 to 2000 (N = 31,524 pairs), where one or both twins had a diagnosis in the schizophrenia spectrum. We defined two groups consisting of; N = 788 twin pairs (affected with schizophrenia spectrum) and a subsample of N = 448 (affected with schizophrenia). Survival analysis was applied to investigate the effect of age at illness onset. Findings: We found that early age at illness onset compared to later onset in the first diagnosed twin can be considered a major risk factor for developing schizophrenia in the second twin. Additionally, we found that the stronger genetic component in MZ twins compared to DZ twins is manifested in the proximity of assigned diagnosis within pairs. Discussion: Early onset schizophrenia could be linked to a more severe genetic predisposition, indicating that age might be perceived as a clinical marker for genetic vulnerability for the illness

A large population-based investigation into the genetics of susceptibility to gastrointestinal infections and the link between gastrointestinal infections and mental illness.

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10-25). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10-8), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine

Гестационный транзиторный тиреотоксикоз

Приведены современные данные литературы о гестационном транзиторном тиреотоксикозе. Освещены особенности гормональной регуляции щитовидной железы.Modern literature data about gestation thyrotoxicosis are presented. The peculiarities of hormonal regulation of the thyroid gland are featured