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Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410^6.30×30K Variant in the Histamine H₁ Receptor.

ABSTRACT: The Exome Aggregation Consortium has collected the protein-encoding DNA sequences of almost 61,000 unrelated humans. Analysis of this dataset for G protein-coupled receptor (GPCR) proteins (available at GPCRdb) revealed a total of 463 naturally occurring genetic missense variations in the histamine receptor family. In this research, we have analyzed the distribution of these missense variations in the four histamine receptor subtypes concerning structural segments and sites important for GPCR function. Four missense variants R127^3.52×52H, R139^34.57×57H, R409^6.29×29H, and E410^6.30×30K, were selected for the histamine H₁ receptor (H₁R) that were hypothesized to affect receptor activity by interfering with the interaction pattern of the highly conserved D(E)RY motif, the so-called ionic lock. The E410^6.30×30K missense variant displays higher constitutive activity in G protein signaling as compared to wild-type H₁R, whereas the opposite was observed for R127^3.52×52H, R139^34.57×57H, and R409^6.29×29H. The E410^6.30×30K missense variant displays a higher affinity for the endogenous agonist histamine than wild-type H₁R, whereas antagonist affinity was not affected. These data support the hypothesis that the E410^6.30×30K mutation shifts the equilibrium towards active conformations. The study of these selected missense variants gives additional insight into the structural basis of H₁R activation and, moreover, highlights that missense variants can result in pharmacologically different behavior as compared to wild-type receptors and should consequently be considered in the drug discovery process.

SUBMITTER: Ma X

PROVIDER: S-EPMC8038156 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increased neuron telencephalic differentiation during deep cortical layer formation has been reported in embryos from diabetic mice. Transitory histaminergic neurons within the mesencephalon/rhombencephalon are responsible for fetal histamine synthesis during development, fibers from this system arrives to the frontal and parietal cortex at embryo day (E) 15. Histamine is a neurogenic factor for cortical neural stem cells in vitro through H1 receptor (H1R) which is highly expressed during corticogenesis in rats and mice. Furthermore, in utero administration of an H1R antagonist, chlorpheniramine, decreases the neuron markers microtubuline associated protein 2 (MAP2) and forkhead box protein 2. Interestingly, in the diabetic mouse model of diabetes induced with streptozotocin, an increase in fetal neurogenesis in terms of MAP2 expression in the telencephalon is reported at E11.5. Because of the reported effects on cortical neuron differentiation of maternal diabetes in one hand and of histamine in the other, here the participation of histamine and H1R on the increased dorsal telencephalic neurogenesis was explored. First, the increased neurogenesis in the dorsal telencephalon at E14 in diabetic rats was corroborated by immunohistochemistry and Western blot. Then, changes during corticogenesis in the level of histamine was analyzed by ELISA and in H1R expression by qRT-PCR and Western blot and, finally, we tested H1R participation in the increased dorsal telencephalic neurogenesis by the systemic administration of chlorpheniramine. Our results showed a significant increase of histamine at E14 and in the expression of the receptor at E12. The administration of chlorpheniramine to diabetic rats at E12 prevented the increased expression of ?III-tubulin and MAP2 mRNAs (neuron markers) and partially reverted the increased level of MAP2 protein at E14, concluding that H1R have an important role in the increased neurogenesis within the dorsal telencephalon of embryos from diabetic rats. This study opens new perspective on the participation of HA and H1R receptor in early corticogenesis in health and disease.

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Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410^6.30×30K Variant in the Histamine H₁ Receptor.

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Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E4106.30×30K Variant in the Histamine H1 Receptor.

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Analysis of Missense Variants in the Human Histamine Receptor Family Reveals Increased Constitutive Activity of E410^6.30×30K Variant in the Histamine H₁ Receptor.