The effect of ionic strength on cardiac muscarinic receptors

Burgen, A. S. V.

doi:10.1111/j.1476-5381.1986.tb10223.x

Cited by 10 publications

(8 citation statements)

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“…The conversion of SH and H forms into L by raised ionic strength (Burgen, 1986) can also be explained on the interaction with auxiliary proteins and a minimalist view would suggest that the same proteins are involved. It is interesting therefore that H to L conversion was distinguishable by greater resistance to ionic strength than the SH to L. The usual binding constants is assumption would be that the ancillary protein conbe seen that there are trols the conformation of the receptor.…”

Section: Resultsmentioning

confidence: 99%

“…The membrane preparations were from the whole heart of rats as described by Burgen (1986 Tables 1-3. Calculations for a system in which the receptor was associated with a second subunit, which modified its affinity, were carried out using a procedure essentially the same as that described by Lee et al (1986). Like these authors we did not find that this method of analysis gave results that stood up to tests of internal consistency and they will not be used in the analysis presented.…”

Section: Methodsmentioning

confidence: 99%

“…The membrane preparations were from the whole heart of rats as described by Burgen (1986). All determinations were made in a buffer consisting of 100mM NaCl, 2mM MgCI2 and 20mM Tris HCl adjusted to pH 7.5.…”

Section: Methodsmentioning

confidence: 99%

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The effects of agonists on the components of the cardiac muscarinic receptor

Burgen

1987

British J Pharmacology

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1 The binding of eleven agonists to muscarinic receptors in the rat heart has been measured in competition with [3H]-N-methylscopolamine. 2 Full analysis of binding required the resolution of three components (SH, H and L). 3 The proportion of the H component was independent of agonist structure. The proportion of the SH component ranged from 2-36% of the total and was dependent on the agonist. The proportion of the L component varied in a complementary way from 59-22% of the total. 4 The ratios of the affinities of ten of the agonists to the three components of the receptors were constant; the weakest binding agonist, choline, had lower ratios of affinity. 5 When saturated with guanylylimidodiphosphate (GppNHp) the SH receptor population was no longer detectable and the H receptor population was reduced by 63%: about 85% ofthe receptors was in the L population. 6 The affinity constants of agonists for the H and L forms of the receptors were not changed by GppNHp. 7 The results are interpreted in terms of the effects of accessory proteins on the proportions of binding and non-binding conformations of the receptor.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The effects of agonists on the components of the cardiac muscarinic receptor

Burgen

1987

British J Pharmacology

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“…The reason for this discrepancy is uncertain, but may reflect differences in species used or methodology adopted, or may be due to the fact that v hen using a low concentration of radioligand (0. (Hulme et al, 1981). The reasons for the difference in the KD values obtained in the two buffer systems is uncertain, although Burgen (1986) has shown that increasing ionic strength can decrease the affinity of antagonists for rat cardiac muscarinic receptors. However, it should also be noted that Hosey (1982) has demonstrated an opposite effect of increasing ionic concentration at chick cardiac muscarinic receptors.…”

Section: Discussionmentioning

confidence: 99%

Direct binding studies on ileal and cardiac muscarinic receptors

Michel¹,

Whiting²

1987

British J Pharmacology

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1 Functional studies have indicated that muscarinic receptors in cardiac tissue differ from those in the ileum. In the present study ileal and cardiac muscarinic receptors identified by [3H]-N-methyl scopolamine ([3H]-NMS) were characterized and the selectivity of currently available ileal and atrial selective antagonists determined. 2 In terms of the current functional classification of muscarinic receptors both ileal and cardiac muscarinic receptors were of the M2 subtype based upon their low affinity for pirenzepine. 3 Cyclohexylphenyl(2-piperidinoethyl)silanol (CPPS), a highly ileal selective antagonist in functional studies, was unable to distinguish between ileal and atrial muscarinic receptors identified in binding studies. Furthermore, although AF-DX 116 and dicyclomine were able to differentiate atrial and ileal muscarinic receptors, neither compound was more than 2 fold selective. These data indicate that it is not possible to subclassify ileal and atrial muscarinic receptors using direct ligand binding studies with these antagonists. 4 In circular ileal smooth muscle, apparent heterogeneity of the M2 muscarinic receptor population was observed. Thus AF-DX 116 identified two populations of sites with affinities differing by 30 fold. These two populations of M2 muscarinic receptors may represent the typical M2 muscarinic receptors identified in cardiac tissue and the more recently discovered 'gland type' M2 muscarinic receptors. 5 The circular ileal smooth muscle tissue homogenate was able to decrease dramatically the apparent affinity of adiphenine. This activity, which appeared to result from a phenylmethylsulphonylfluoride (PMSF) sensitive protease effect, should be considered when conducting studies using this tissue preparation and compounds of similar structure to adiphenine.

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“…These different forms of the receptor seemed stable because when we inactivated one form, the residual forms did not reestablish the proportions. On the other hand, we could convert the forms with the highest affinity into the lower-affinity forms by simply raising the ionic strength (16). When cardiac receptors were examined, the situation seemed similar, but it was not just high-ionic strength that could convert the higher-into the lower-affinity forms.…”

Section: Professor Of Pharmacology In Cambridgementioning

confidence: 98%

Targets of Drug Action

Burgen

2000

Annu. Rev. Pharmacol. Toxicol.

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This article considers early work from the author's laboratory on muscarinic receptor specificity, subtypes, and conformational variability, with the use of nuclear magnetic resonance in pharmacology and the conformational variants of dihydrofolate reductase and general questions of receptors. It also considers some current approaches to drug development and receptor function, particularly as influenced by increasing knowledge of three-dimensional structure of receptors. A CHANGE OF PLANSLike many pharmacologists, my original training was in medicine, and I fully expected to spend my career in clinical work, as a pediatrician. However, immediately after graduation in London, I was seriously ill and one of my frequent visitors was my professor of physiology, Samson Wright. He persuaded me not to go straight into clinical work on recovery but to spend some time in a laboratory. What about joining the new pharmacology department at the Middlesex Hospital Medical School that Cyril Keele was just establishing? he asked. I said that I would, for a year only, but then I got hooked. I began attending the monthly meetings of the Physiological Society (in those days there was no separate pharmacological society), and the major topics presented were concerned with the growing evidence that the role of acetylcholine as a transmitter could be extended from the parasympathetic postganglionic endings to the sympathetic ganglia and the neuromuscular junction. The experimental evidence in favor was developed by WS Feldberg, GL Brown, Bernard Katz, and FC MacIntosh under the genial, but critical approval of our doyen, Sir Henry Dale. These developments were strenuously opposed by JC Eccles, who held to the all electrical theory of synaptic transmission and that all the acetylcholine effects people were looking at were ''epiphenomena.'' This in no way discomforted Feldberg, who wrote of the extension of the theory to the central nervous system with great confidence: ''The present position of the theory of acetylcholine as central transmitter is all but settled.'' Later he added a bit of caution: ''perhaps not the universal central transmitter.'' This all made for a very exciting time, and quite naturally I found myself Annu. Rev. Pharmacol. Toxicol. 2000.40:1-16. Downloaded from www.annualreviews.org Access provided by 52.183.12.225 on

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The effect of ionic strength on cardiac muscarinic receptors

Cited by 10 publications

References 13 publications

The effects of agonists on the components of the cardiac muscarinic receptor

The effects of agonists on the components of the cardiac muscarinic receptor

Direct binding studies on ileal and cardiac muscarinic receptors

Targets of Drug Action

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