Muscarinic Receptors Modulate Dopamine‐Activated Adenylate Cyclase of Rat Striatum

Olianas, Maria C.; Onali, Pierluigi; Neff, Norton H.; Costa, E.

doi:10.1111/j.1471-4159.1983.tb00834.x

Cited by 39 publications

(20 citation statements)

References 15 publications

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“…The picomolar/¢D values obtained in the above study were in marked contrast to the micromolar constants obtained by measurement of tissue responses to musearinic stimulation (see [13][14][15] for some recent references). Certainly° this is not surprizing since one could hardly expect a direct interrelation between ligand-induced fluidity changes at 25°C and biochemical or physiological responses at 37°C.…”

Section: R B Molecules/cellscontrasting

confidence: 70%

Lipid domain reorganization and receptor events Results obtained with new fluorescent lipid probes

Bergel'son¹

1992

FEBS Letters

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Binding of a ligand to the extracellular site of a membrane receptor involves conformational changes not only of the extracellular and cytoplasmic sites but also of the membrane-spanning segments of the receptor protein. The lipids forming the environment of the trans-membrane receptor segments, being flexible and mobile, must follow the shape changes of the receptor molecule to some extent. For this reason ligandreceptor binding itself can be expected to result in changes of the packing of lipid molecules surrounding the receptor. Since lipids are organized in a cooperative manner such changes may affect large areas of the membrane and hence can be registered by physical methods. It has been stated repeatedly that binding of various ligands including hormones, antibodies or lectins to membrane-associated receptors is accompanied by fluidity changes of the target membrane [1][2][3].The aim of this article is to summarize recent evidence suggesting that in highly heterogeneous biological membranes containing numerous metastable lipid domains and/or clusters conformational changes of membrane-associated proteins may result not only in global fluidity changes but also in alterations of the supramolecular lipid domain organization. Frequently such changes can be tbllowed by using, as fluorescent probe, analogs of natural membrane phospholipids or glycolipids bearing, at the end of one of the fatty acyl chains, a 9.anthrylvinyl (AV) group ( cells, and in the latter case may reside for a relatively long time in the plasma membrane without internalization [7].In comparison to most other fluorophores used in membrane research, the AV group displays important advantages. It causes little disturbance because it is nonpolar, flat, and relatively compact. When attached to the fatty acyl chain at an appropriate distance from the head group the AV-fluorophores reside uniformly and exclusively in the center of the bilayer where the host lipids are packed most loosely, and affect neither the mobility nor the orientation and conformation of the major part of the molecules of the surrounding host lipids including their head groups [8]. The AV-group is characterized also by high quantum yields and very short fluorescence lifetimes [9]. The latter property makes the AV-fluorophore suitable for fluorescence polarization measurements. Moreover, in phospholipid bilayers the restricted rotational diffusion of the AVlabeled lipid molecules is of the same time scale as the fluorescence decay. Therefore even subtle changes in the fluidity of the probes microenvironment produce considerable changes in the polarization of fluorescence. The fluorescent parameters of the AV-group (,~ 365 nm, A,~m 430 rim; high extinction coefficient) make it also a highly efficient acceptor for resonance energy transfer (RET) from nearby tryptophans. Since the distance that RET can occur over is as long as 5 nm while RET efficiency depends on the sixth power of the donoracceptor distance, RET measurements with AV-labeled lipids permits the following of even e...

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Section: R B Molecules/cellscontrasting

confidence: 70%

Lipid domain reorganization and receptor events Results obtained with new fluorescent lipid probes

Bergel'son¹

1992

FEBS Letters

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“…Furthermore, whilst it is relatively easy to identify antagonists, partial agonists and full agonists it is often more difficult to distinguish differing degrees of partial agonism without detailed secondary biochemical tests e.g. phosphatidyl-inositol turnover or adenylate cyclase assays (Olianas et al, 1983;Fisher et al, 1984).…”

Section: Introductionmentioning

confidence: 99%

Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo‐M ratio as an index of efficacy at cortical muscarinic receptors

Freedman

Harley

Iversen

1988

British J Pharmacology

112

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3 Full agonists such as carbachol and muscarine possessed a ratio ofpotencies against the antagonist versus the agonist ligand (NMS/Oxo-M ratio) of >4000. 4 Compounds which have been shown previously to display partial agonist activity in functional assays e.g. pilocarpine and RS86 had intermediate NMS/Oxo-M ratios of 100-150. A second group of compounds which included oxotremorine had somewhat higher ratios (500-1400). 5 The ratio of affinity constants for the two assays predicted the ability of agonists to stimulate cortical phosphatidyl-inositol turnover. 6 These results suggest that the NMS/Oxo-M ratio may be a useful prediction of efficacy for novel compounds acting at cortical muscarinic receptors.

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“…Activation of muscarinic cholinoceptor has been reported to inhibit adenylyl cyclase activity in different rat brain areas, such as corpus striatum (Olianas et al, 1983), cerebral cortex (McKinney et al, 1991) and hippocampus (Vickroy & Cadman, 1989). However, in rat olfactory bulb, muscarinic receptor agonists cause stimulation, rather than inhibition, of basal adenylyl cyclase activity .…”

Section: Introductionmentioning

confidence: 99%

Antagonism by (R)‐ and (S)‐trihexyphenidyl of muscarinic stimulation of adenylyl cyclase in rat olfactory bulb and inhibition in striatum and heart

Onali

Aasen

Olianas

1994

British J Pharmacology

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1 Activation of muscarinic receptors in rat olfactory bulb stimulates adenylyl cyclase activity. This response was competitively antagonized by the (R)-and (S)-enantiomers of trihexyphenidyl with pA2 values of 8.84 and 6.09, respectively. 2 Similarly, in rat striatal homogenates, muscarinic inhibition of adenylyl cyclase activity was antagonized by the (R)-and (S)-enantiomers with pA2 values of 8.75 and 6.12, respectively. 3 In contrast, in rat myocardium the muscarinic inhibition of the adenosine 3':5'-cyclic monophosphate (cyclic AMP) formation was more weakly antagonized by trihexyphenidyl, with a particularly marked loss (15 fold) in activity of the (R)-enantiomer. The (R)-and (S)-enantiomers had pA2 values of 7.64 and 5.72, respectively. 4 Each muscarinic response was completely antagonized by increasing concentrations of (R)-trihexyphenidyl with a Hill coefficient not significantly different from unity. 5 The present study shows that the muscarinic receptors coupled to stimulation of adenylyl cyclase in the olfactory bulb display high stereoselectivity for the enantiomers of trihexyphenidyl. The affinities of these receptors for the antagonists are similar to those shown by the striatal receptors. This finding supports the hypothesis that both the muscarinic stimulation of adenylyl cyclase in the olfactory bulb and the muscarinic inhibition of the enzyme in striatum are mediated by activation of a receptor subtype pharmacologically equivalent to the m4 gene product. On the other hand, the weaker affinities and the lower stereoselectivity for the trihexyphenidyl enantiomers exhibited by the muscarinic inhibition of adenylyl cyclase in the heart are consistent with the involvement of M2 receptors in this response.

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Muscarinic Receptors Modulate Dopamine‐Activated Adenylate Cyclase of Rat Striatum

Cited by 39 publications

References 15 publications

Lipid domain reorganization and receptor events Results obtained with new fluorescent lipid probes

Lipid domain reorganization and receptor events Results obtained with new fluorescent lipid probes

Relative affinities of drugs acting at cholinoceptors in displacing agonist and antagonist radioligands: the NMS/Oxo‐M ratio as an index of efficacy at cortical muscarinic receptors

Antagonism by (R)‐ and (S)‐trihexyphenidyl of muscarinic stimulation of adenylyl cyclase in rat olfactory bulb and inhibition in striatum and heart

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