About: Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System

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About: Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System
Creator	Schneider, Erich Seifert, Roland
topic	covid:eef81233541c4504a9dc542873a5a8dca4a313e6#this
Source	PMC
abstract	A large problem of histamine receptor research is data heterogeneity. Various experimental approaches, the complex signaling pathways of mammalian cells, and the use of different species orthologues render it difficult to compare and interpret the published results. Thus, the four human histamine receptor subtypes were analyzed side-by-side in the Sf9 insect cell expression system, using radioligand binding assays as well as functional readouts proximal to the receptor activation event (steady-state GTPase assays and [(35)S]GTPγS assays). The human H(1)R was co-expressed with the regulators of G protein signaling RGS4 or GAIP, which unmasked a productive interaction between hH(1)R and insect cell Gα(q). By contrast, functional expression of the hH(2)R required the generation of an hH(2)R-Gsα fusion protein to ensure close proximity of G protein and receptor. Fusion of hH(2)R to the long (Gsα(L)) or short (Gsα(S)) splice variant of Gα(s) resulted in comparable constitutive hH(2)R activity, although both G protein variants show different GDP affinities. Medicinal chemistry studies revealed profound species differences between hH(1)R/hH(2)R and their guinea pig orthologues gpH(1)R/gpH(2)R. The causes for these differences were analyzed by molecular modeling in combination with mutational studies. Co-expression of the hH(3)R with Gα(i1), Gα(i2), Gα(i3), and Gα(i/o) in Sf9 cells revealed high constitutive activity and comparable interaction efficiency with all G protein isoforms. A comparison of various cations (Li(+), Na(+), K(+)) and anions (Cl(−), Br(−), I(−)) revealed that anions with large radii most efficiently stabilize the inactive hH(3)R state. Potential sodium binding sites in the hH(3)R protein were analyzed by expressing specific hH(3)R mutants in Sf9 cells. In contrast to the hH(3)R, the hH(4)R preferentially couples to co-expressed Gα(i2) in Sf9 cells. Its high constitutive activity is resistant to NaCl or GTPγS. The hH(4)R shows structural instability and adopts a G protein-independent high-affinity state. A detailed characterization of affinity and activity of a series of hH(4)R antagonists/inverse agonists allowed first conclusions about structure/activity relationships for inverse agonists at hH(4)R. In summary, the Sf9 cell system permitted a successful side-by-side comparison of all four human histamine receptor subtypes. This chapter summarizes the results of pharmacological as well as medicinal chemistry/molecular modeling approaches and demonstrates that these data are not only important for a deeper understanding of H(x)R pharmacology, but also have significant implications for the molecular pharmacology of GPCRs in general.
has issue date	2017-02-24(xsd:dateTime)
bibo:doi	10.1007/164_2016_124
bibo:pmid	28233175
has license	no-cc
sha1sum (hex)	eef81233541c4504a9dc542873a5a8dca4a313e6
schema:url	https://doi.org/10.1007/164_2016_124
resource representing a document's title	Pharmacological Characterization of Human Histamine Receptors and Histamine Receptor Mutants in the Sf9 Cell Expression System
has PubMed Central identifier	PMC7120522
has PubMed identifier	28233175
schema:publication	Histamine and Histamine Receptors in Health and Disease
resource representing a document's body	covid:eef81233541c4504a9dc542873a5a8dca4a313e6#body_text
is http://vocab.deri.ie/void#inDataset of	proxy:http/ns.inria.fr/covid19/eef81233541c4504a9dc542873a5a8dca4a313e6
is schema:about of	named entity 'expression' named entity 'assays' named entity 'insect' named entity 'RGS4' named entity 'species' named entity 'steady-state' named entity 'large' named entity 'INTERACTION' named entity 'USED' named entity 'GENERATION' named entity 'PARTS' named entity 'EXPERIMENTAL' named entity 'SIGNALING PATHWAYS' named entity 'LARGE' named entity 'histamine receptor' named entity 'cells' named entity 'assays' named entity 'compare' named entity 'thesis' named entity 'human' named entity 'histamine receptor' named entity 'radioligand binding' named entity 'signaling pathways' named entity 'Histamine Receptors' named entity 'histamine' named entity 'chemokine receptor' named entity 'agonist' named entity 'rat' named entity 'Constitutive activity' named entity 'expression levels' named entity 'protein' named entity 'ligand' named entity 'constitutive activity' named entity 'chaperone' named entity 'wild-type' named entity 'fusion protein' named entity 'GDP' named entity 'agonists' named entity 'ligand' named entity 'Potencies' named entity 'constitutive activity' named entity 'protein' named entity 'guanidine' named entity 'binding pocket' named entity 'co-expression' named entity 'Regulator of G protein signaling' named entity 'mutation' named entity 'agonists' named entity 'potency' named entity 'GTPγS' named entity 'Sf9' named entity 'Co-expression' named entity 'GPCRs' named entity 'protein' named entity 'agonist' named entity 'steady-state' named entity 'protein' named entity 'cell membranes' named entity 'solubilization' named entity 'interact' named entity 'G-protein' named entity 'amino acid' named entity 'GTPase' named entity 'molecule' named entity 'Gβγ' named entity 'Constitutive activity' named entity 'pharmacological' named entity 'Western blot' named entity 'isoforms' named entity 'proxyfan' named entity 'cell membranes' named entity 'insect' named entity 'molecular modelling' named entity 'GTPase' named entity 'histamine' named entity 'GTPase' named entity 'agonist' named entity 'GTPase'

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