Biomaterial Database

Investigation of I1-imidazoline receptors using microphysiometry and molecular modelling. 1998

I F Musgrave, and R A Hughes

Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia. ian.musgrave@med.monash.edu.au

The molecular identity and structure of imidazoline receptors is still poorly understood. For example the I1-imidazoline binding site (I1-site) is localised to the plasma membrane, but it is not clear if this represents a conventional receptor. The I1-site reportedly has both high and low affinity binding states. Again it is not clear if these sites represent different states of the same receptor, or distinct molecular entities. The signal transduction mechanisms of I1-imidazoline receptors are beginning to be unravelled. There is clear evidence that ligands with high affinity for I1-sites stimulate phosphatidylcholine-selective phospholipase C in the rat adrenal medullary tumour cell line PC-12, but this may not be the case in all cell types. We investigated the possible role of this novel pathway in bovine adrenal medullary cells. Radioligand binding studies with [3H]clonidine confirmed the presence of I1-sites in membranes from these cells. Using microphysiometry, a recently developed technique for determining cellular activation, the extracellular acidification rates of cultured bovine adrenal medullary cells were unaffected by a number of imidazolines considered to be agonists at the I1-site. This suggests that there is no I1-site mediated stimulation of phosphatidylcholine specific phospholipase C in these cells. However, nicotine-stimulated increases in extracellular acidification were blocked by 100 microM clonidine. Ion channels have been suggested as another possible I1-imidazoline 'receptor' family, and may represent the low affinity I1-site detected in binding studies. I1-Site ligands can be shown to bind to, or block, several members of the ligand-gated ion channel superfamily, including the 5HT3, K+ATP, NMDA and nicotinic acetylcholine receptors. The I1-site ligands appear to be binding to, and acting at, the previously described phencyclidine binding site in these channels. Furthermore, molecular modelling suggests that I1-site selective ligands share a common three-dimensional structure with phencyclidine, and that I2-site selective ligands do not have this structure. This suggests that a phencyclidine-binding site motif may represent a novel site of action for I1-site ligands, and a search for receptors based on this motif may reveal novel imidazoline 'receptors'.

UI	MeSH Term	Description	Entries
D007093	Imidazoles	Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).
D008024	Ligands	A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)	Ligand
D008958	Models, Molecular	Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.	Molecular Models,Model, Molecular,Molecular Model
D008968	Molecular Conformation	The characteristic three-dimensional shape of a molecule.	Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D011869	Radioligand Assay	Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders).	Protein-Binding Radioassay,Radioreceptor Assay,Assay, Radioligand,Assay, Radioreceptor,Assays, Radioligand,Assays, Radioreceptor,Protein Binding Radioassay,Protein-Binding Radioassays,Radioassay, Protein-Binding,Radioassays, Protein-Binding,Radioligand Assays,Radioreceptor Assays
D011955	Receptors, Drug	Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.	Drug Receptors,Drug Receptor,Receptor, Drug
D002417	Cattle	Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.	Beef Cow,Bos grunniens,Bos indicus,Bos indicus Cattle,Bos taurus,Cow,Cow, Domestic,Dairy Cow,Holstein Cow,Indicine Cattle,Taurine Cattle,Taurus Cattle,Yak,Zebu,Beef Cows,Bos indicus Cattles,Cattle, Bos indicus,Cattle, Indicine,Cattle, Taurine,Cattle, Taurus,Cattles, Bos indicus,Cattles, Indicine,Cattles, Taurine,Cattles, Taurus,Cow, Beef,Cow, Dairy,Cow, Holstein,Cows,Dairy Cows,Domestic Cow,Domestic Cows,Indicine Cattles,Taurine Cattles,Taurus Cattles,Yaks,Zebus
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
D002540	Cerebral Cortex	The thin layer of GRAY MATTER on the surface of the CEREBRAL HEMISPHERES that develops from the TELENCEPHALON and folds into gyri and sulci. It reaches its highest development in humans and is responsible for intellectual faculties and higher mental functions.	Allocortex,Archipallium,Cortex Cerebri,Cortical Plate,Paleocortex,Periallocortex,Allocortices,Archipalliums,Cerebral Cortices,Cortex Cerebrus,Cortex, Cerebral,Cortical Plates,Paleocortices,Periallocortices,Plate, Cortical
D003000	Clonidine	An imidazoline sympatholytic agent that stimulates ALPHA-2 ADRENERGIC RECEPTORS and central IMIDAZOLINE RECEPTORS. It is commonly used in the management of HYPERTENSION.	Catapres,Catapresan,Catapressan,Chlophazolin,Clofelin,Clofenil,Clonidine Dihydrochloride,Clonidine Hydrochloride,Clonidine Monohydrobromide,Clonidine Monohydrochloride,Clopheline,Dixarit,Gemiton,Hemiton,Isoglaucon,Klofelin,Klofenil,M-5041T,ST-155,Dihydrochloride, Clonidine,Hydrochloride, Clonidine,M 5041T,M5041T,Monohydrobromide, Clonidine,Monohydrochloride, Clonidine,ST 155,ST155