Biomaterial Database

Role of G-protein availability in differential signaling by alpha 2-adrenoceptors. 2001

J Nasman, and J P Kukkonen, and S Ammoun, and K E Akerman

Department of Physiology, Division of Cell Physiology, Uppsala University, BMC, Box 572, SE-75123, Uppsala, Sweden. Johnny.Nasman@fysiologi.uu.se

The impact of G-protein expression on the coupling specificity of the human alpha(2B)-adrenergic receptor (alpha(2B)-AR) was studied in Sf9 cells. The alpha(2B)-AR was shown to activate both coexpressed G(s)- and G(i)-proteins in a [(35)S]GTPgammaS binding assay. Noradrenaline and the synthetic agonist UK14,304 were equally potent and efficacious in stimulating G(i) activation. At the effector level (adenylyl cyclase), both ligands stimulated cAMP production. In the presence of forskolin, the effects of the agonists were more complex. Noradrenaline stimulated cAMP production, while UK14,304 showed a biphasic concentration-response curve with inhibition of stimulated cAMP production at low agonist concentrations and further stimulation at high agonist concentrations. G(s) coexpression caused a monophasic stimulatory response with both ligands. Coexpression with G(i) resulted in a biphasic concentration-response curve for noradrenaline and a monophasic inhibition with UK14,304. Experiments with a panel of agonists demonstrated that the more efficacious an agonist is in stimulating cAMP production, the weaker is its ability to couple to inhibition of cAMP accumulation via exogenous G(i). To be able to explain the mechanistic consequences of dual G-protein coupling described above, we developed a mathematical model based on the hypothesis that an agonist induces different conformations of the receptor having different affinity for different G-proteins. The model reproduced the profiles seen in the concentration-response curves with G(s) and G(i) coexpression. The model predicts that the affinity of the receptor conformation for G-proteins as well as the availability of G-proteins will determine the ultimate response of the receptor.

UI	MeSH Term	Description	Entries
D007313	Insecta	Members of the phylum ARTHROPODA composed or organisms characterized by division into three parts: head, thorax, and abdomen. They are the dominant group of animals on earth with several hundred thousand different kinds. Three orders, HEMIPTERA; DIPTERA; and SIPHONAPTERA; are of medical interest in that they cause disease in humans and animals. (From Borror et al., An Introduction to the Study of Insects, 4th ed, p1).	Insects,Insect
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D003198	Computer Simulation	Computer-based representation of physical systems and phenomena such as chemical processes.	Computational Modeling,Computational Modelling,Computer Models,In silico Modeling,In silico Models,In silico Simulation,Models, Computer,Computerized Models,Computer Model,Computer Simulations,Computerized Model,In silico Model,Model, Computer,Model, Computerized,Model, In silico,Modeling, Computational,Modeling, In silico,Modelling, Computational,Simulation, Computer,Simulation, In silico,Simulations, Computer
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000242	Cyclic AMP	An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.	Adenosine Cyclic 3',5'-Monophosphate,Adenosine Cyclic 3,5 Monophosphate,Adenosine Cyclic Monophosphate,Adenosine Cyclic-3',5'-Monophosphate,Cyclic AMP, (R)-Isomer,Cyclic AMP, Disodium Salt,Cyclic AMP, Monoammonium Salt,Cyclic AMP, Monopotassium Salt,Cyclic AMP, Monosodium Salt,Cyclic AMP, Sodium Salt,3',5'-Monophosphate, Adenosine Cyclic,AMP, Cyclic,Adenosine Cyclic 3',5' Monophosphate,Cyclic 3',5'-Monophosphate, Adenosine,Cyclic Monophosphate, Adenosine,Cyclic-3',5'-Monophosphate, Adenosine,Monophosphate, Adenosine Cyclic
D000262	Adenylyl Cyclases	Enzymes of the lyase class that catalyze the formation of CYCLIC AMP and pyrophosphate from ATP.	Adenyl Cyclase,Adenylate Cyclase,3',5'-cyclic AMP Synthetase,Adenylyl Cyclase,3',5' cyclic AMP Synthetase,AMP Synthetase, 3',5'-cyclic,Cyclase, Adenyl,Cyclase, Adenylate,Cyclase, Adenylyl,Cyclases, Adenylyl,Synthetase, 3',5'-cyclic AMP
D000316	Adrenergic alpha-Agonists	Drugs that selectively bind to and activate alpha adrenergic receptors.	Adrenergic alpha-Receptor Agonists,alpha-Adrenergic Receptor Agonists,Adrenergic alpha-Agonist,Adrenergic alpha-Receptor Agonist,Receptor Agonists, Adrenergic alpha,Receptor Agonists, alpha-Adrenergic,alpha-Adrenergic Agonist,alpha-Adrenergic Agonists,alpha-Adrenergic Receptor Agonist,Adrenergic alpha Agonist,Adrenergic alpha Agonists,Adrenergic alpha Receptor Agonist,Adrenergic alpha Receptor Agonists,Agonist, Adrenergic alpha-Receptor,Agonist, alpha-Adrenergic,Agonist, alpha-Adrenergic Receptor,Agonists, Adrenergic alpha-Receptor,Agonists, alpha-Adrenergic,Agonists, alpha-Adrenergic Receptor,Receptor Agonist, alpha-Adrenergic,Receptor Agonists, alpha Adrenergic,alpha Adrenergic Agonist,alpha Adrenergic Agonists,alpha Adrenergic Receptor Agonist,alpha Adrenergic Receptor Agonists,alpha-Agonist, Adrenergic,alpha-Agonists, Adrenergic,alpha-Receptor Agonist, Adrenergic,alpha-Receptor Agonists, Adrenergic
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D014162	Transfection	The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.	Transfections
D015398	Signal Transduction	The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.	Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal