Calmodulin Plays a Pivotal Role in Cellular Regulation

Cheung, Wai Yiu

doi:10.1126/science.6243188

Cited by 2,402 publications

(797 citation statements)

References 133 publications

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“…Calmodulin is a widely distributed calcium binding protein that may mediate the effect of changes in intracellular calcium ion concentration [28,29]. This protein has recently been identified in rat islets [30,31], and the calmodulin inhibitor trifluoperazine [32] found to inhibit insulin secretion [30].…”

Section: Discussionmentioning

confidence: 99%

Insulin secretion by a transplantable rat islet cell tumour

et al. 1981

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Summary. Investigation of the subcellular and molecular components of insulin secretion has been made difficult by the small quantities of material available. The recent development of a transplantable rat islet cell tumour of high insulin content and state of differentiation suggested a system more amenable to analysis. To validate the tumour as a model of secretion we have studied its release of insulin. In acute experiments in vitro immunoreactive insulin release was increased by leucine, glucagon, theophylline and dibutyryl cyclic AMP, though not by glucose. Leucine (20 mmol/1) plus theophylline (5 mmol/1) caused an abrupt, sustained and rapidly reversible stimulation of two-to fivefold. The response was inhibited by antagonists of cellular oxidative phosphorylation (cyanide, 2,4--dinitrophenol, antimycin A), calcium flux (EGTA, verapamil, Mg2 § calmodulin (trifluoperazine), microtubules (vinblastine, colchicine) and by adrenaline and somatostatin. These findings suggest that the tumour secretes insulin by an exocytotic mechanism similar to that of normal islet tissue. Key words: Islet cell tumour, B cell, insulin secretionThe pancreatic B cell has proved difficult to investigate at the subcellular and molecular levels. The classical strategy of subcellular fractionation, purification and reassembly has been greatly hindered by the shortage of starting material [3,4]. In this context the description recently of a transplantable rat islet cell tumour is of considerable interest. The tumour contains large amounts of insulin and consists predominantly of well-granulated cells the morphology of which closely resembles that of rat B cells [1,2].That this islet cell tumour might offer a largescale model of insulin secretion is an attractive possibility. Realisation of this potential, however, depends upon establishing that the tumour is indeed capable of the exocytosis of insulin. We here report a series of experiments in which the characteristics of insulin release by the turnout were defined. The effect of putative secretagogues, the dynamics of insulin release, and the influence of potentiators and inhibitors of secretion are described. Materials and MethodsThe islet cell tumour [1, 2] was maintained by serial subcutaneous transplantation within a colony of inbred albino NEDH strain rats [2]. BuffersTissue was handled in a Krebs Ringer solution [5] containing NaC1 115mmol/1, KC1 5.0mmol/1, NaI-ICO 3 24mmol/1, MgC12 1.0 mmol/1 and CaC12 2.5 mmol/1, freshly equilibrated with 5% CO 2 95% 02. Except where specified glucose 2.8 mmol/l, bovine plasma albumin (Armour Pharmaceuticals, Eastbourne, UK) 1.0 mg/ml, and 5.0 mmol/1 each of sodium pyruvate, monosodium glutamate and disodium fumarate were included (using 95 mmol/l NaC1 to maintain the final sodium ion concentration at 139 mmol/ 1). When individual experiments required further additions the osmolality of control buffers was balanced using sucrose.Chemicals were purchased from Fisons Scientific Apparatus, Loughborough, UK and British Drug House Chemicals, Poole,...

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Section: Discussionmentioning

confidence: 99%

Insulin secretion by a transplantable rat islet cell tumour

et al. 1981

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“…Ca*+, like cyclic AMP, is a pleiotypic mediator that affects a wide variety of cellular processes [48,119]. Therefore co-ordinate control of growth by Ca2+ rather than control of one or two specific events or processes must be considered.…”

Section: Cancer Cell Growthmentioning

confidence: 99%

Cyclic AMP, calcium and control of cell growth

Ralph

1983

FEBS Letters

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The role of cyclic AMP and calcium in the control of normal and tumour cell growth is considered in relation to the question whether cyclic AMP is a true mitogen or cc-mitogen. It is proposed that cyclic AMP normally controls the cell cycle at a point in Gl phase only by virtue of its ability to exclude calcium required by cells to progress past this point into S phase. Therefore increased influx of calcium by other routes induced by various factors can bypass the inhibitory effect of cyclic AMP and stimulate growth. In these circumstances cyclic AMP or calcium may or may not facilitate further progress into S phase according to the metabolic requirements of individual cells. The relevance to cancer cells is considered. Cyclic AMP Calcium

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“…Trifluoperazine has been shown to bind to calmodulin with high affinity [20] and has been used as a specific calmodulin antagonist [8]. I was unable to show a specific effect of trifluoperazine on phosphorylation-induced receptor loss since preincubation with 100 PM trifluoperazine, a level shown to inhibit calmodulin-stimulated protein kinase activity [2 1,221, completely abolished ['HI QNB binding.…”

Section: Effect Of Exogenous Calmodulin On Phosphorylation-induced Rementioning

confidence: 99%

“…Calmodulin is a small heat-stable calcium-binding protein demonstrated to be involved in a wide range of systems regulated by Ca'+ [8,9]. Immunocytochemical techniques have demonstrated its presence at central synapses [lo,1 11.…”

Section: Introductionmentioning

confidence: 99%

The loss of muscarinic acetylcholine receptors in synaptic membranes under phosphorylating conditions is dependent on calmodulin

Burgoyne¹

1981

FEBS Letters

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Calmodulin Plays a Pivotal Role in Cellular Regulation

Cited by 2,402 publications

References 133 publications

Insulin secretion by a transplantable rat islet cell tumour

Insulin secretion by a transplantable rat islet cell tumour

Cyclic AMP, calcium and control of cell growth

The loss of muscarinic acetylcholine receptors in synaptic membranes under phosphorylating conditions is dependent on calmodulin

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