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Biomedical subjects

M J Berridge

Publications and source records attributed to M J Berridge.

At least 127 records · Page 7Linked to original sources
PubMed1986

Regulation of ion channels by inositol trisphosphate and diacylglycerol.

Calcium-mobilizing receptors function to regulate ion channels located not only in the plasma membrane but also across the membranes of intracellular organelles, particularly the endoplasmic reticulum. A characteristic feature of such receptors is that they stimulate the hydrolysis of an inositol lipid to generate a pair of second messengers. Diacylglycerol remains within the plasma membrane where it activates protein kinase C leading to the phosphorylation of proteins some of which may regulate specific ionic channels, such as the calcium-dependent potassium channel or the Na+/H+ exchanger which regulates intracellular pH. The inositol trisphosphate (Ins 1,4,5P3) released to the cytosol functions as a second messenger to release calcium from the endoplasmic reticulum. The Ins 1,4,5P3 acts on a specific receptor to enhance the passive efflux of calcium while having no effect on the active calcium pump. There are indications that this Ins 1,4,5P3-induced release of calcium from an internal membrane store might provide an explanation of excitation-contraction coupling in skeletal muscle. Skinned skeletal muscle cells can be induced to contract by adding Ins 1,4,5P3. Mobilization of calcium from intracellular reservoirs by Ins 1,4,5P3 may thus prove to be a ubiquitous and fundamental mechanism for regulating cellular activity.

Animals↗
PubMed1986

Receptor-stimulated inositol phospholipid hydrolysis and neural function.

Many transmitters in the brain act by stimulating the hydrolysis of an inositol lipid (phosphatidylinositol 4,5-bisphosphate) to give diacylglycerol (DG) and inositol 1,4,5-trisphosphate (Ins1,4,5P3). These two second messengers mark the beginning of a highly versatile signalling system which may have a unique role in modulating neural activity. By mobilizing calcium from intracellular stores, Ins 1,4,5P3 may regulate the calcium set-point thereby effecting both excitability and facilitation. The DG/C-kinase pathway, through its ability to modulate a variety of physiological processes, may regulate both transmitter release and excitability. Some of the changes in excitability seem to depend upon changes in potassium permeability. Receptor-stimulated inositol lipid hydrolysis may thus play a central role in neural function by modulating transmitter release through subtle alterations in excitability.

Animals↗
PubMed1986

Growth factors, oncogenes and inositol lipids.

Normal cells require growth factors to multiply. One group of growth factors such as platelet-derived growth factor, bombesin and vasopressin in fibroblasts or antigen in lymphocytes uses a specific inositol lipid as part of a transduction mechanism for generating intracellular mitogenic signals. These growth factors stimulate the hydrolysis of phosphatidylinositol 4,5-bisphosphate to give diacylglycerol (DG) and inositol 1,4,5-trisphosphate (Ins1,4,5P3). The DG remains within the plane of the membrane to activate protein kinase C, one function of which is to increase intracellular pH by switching on a Na+/H+ exchanger. The other product, Ins1,4,5P3, functions as a second messenger to mobilize calcium from intracellular stores. These two ionic events, the increase in pH and calcium, contribute to the onset of DNA synthesis. The hydrolysis of an inositol lipid is a key event in this signal pathway which mediates the action of competence factors. A separate signal pathway, perhaps based on tyrosine phosphorylation, carries out the effects of progression growth factors such as epidermal growth factor (EGF) and insulin. It is argued that oncogenes may be arranged into groups associated with specific signal pathways. For example, the sis oncogene encodes platelet-derived growth factor which might use the src gene product as part of its transduction mechanism to generate the second messengers DG, Ins1,4,5P3 and calcium. These last then act to stimulate the transcription of myc and fos. On the other hand, the erbB gene encodes a protein which resembles the receptor for EGF. The function of the ras protein remains a major unsolved problem but there is indirect evidence for proposing that it may mediate the action of progression factors such as EGF or insulin.

Animals↗
PubMed1985

Relationship between secretagogue-induced Ca2+ release and inositol polyphosphate production in permeabilized pancreatic acinar cells.

We have previously shown that inositol trisphosphate (IP3) releases Ca2+ from a nonmitochondrial pool of permeabilized rat pancreatic acinar cells (Streb, H., Irvine, R. F., Berridge, M. J., and Schulz, I. (1984) Nature 306, 67-69). This pool was later identified as endoplasmic reticulum (Streb, H., Bayerdorffer, E., Haase, W., Irvine, R. F., and Schulz, I. (1984) J. Membr. Biol. 81, 241-253). As IP3 is produced by hydrolysis of phosphatidylinositol bisphosphate on activation of many "Ca2+-mobilizing receptors," our observation supported the proposal that IP3 functions as a second messenger to release Ca2+ from the endoplasmic reticulum. We have here used the same preparation of permeabilized acinar cells to study the relationship of secretagogue-induced Ca2+ release and IP3 production. We show that: 1) secretagogue-induced Ca2+ release in permeabilized cells is accompanied by a parallel production of inositol trisphosphate. 2) When the secretagogue-induced increase in intracellular free Ca2+ concentration was abolished by ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid buffering, secretagogue-induced IP3 production was unimpaired. 3) When secretagogue-induced IP3 production was reduced by inhibiting phospholipase C with neomycin, secretagogue-induced Ca2+ release was also abolished. 4) When the IP3 breakdown was reduced either by lowering the free Mg2+ concentration of the incubation medium or by adding 2.3-diphosphoglyceric acid, the rise in IP3 and the release of Ca2+ induced by secretagogues were both increased. These results further support the role of IP3 as a second messenger to induce Ca2+ mobilization.

2,3-Diphosphoglycerate↗
PubMed1985

Phosphoinositides and cell proliferation.

Certain growth factors act by stimulating the hydrolysis of inositol lipids to yield putative second messengers such as diacylglycerol (DG) and inositol trisphosphate (IP3). One function of the former is to stimulate C-kinase, which may act by switching on a sodium/hydrogen exchanger to induce the increase in pH that appears to have a permissive effect on DNA synthesis. Studies on Swiss 3T3 cells have revealed that growth factors stimulate an increase in two separate isomers of IP3. In addition to inositol 1,4,5-trisphosphate there was a large increase in inositol 1,3,4-trisphosphate. While the former functions to elevate intracellular calcium, which has been implicated in the control of growth of many different cell types, the function of the latter is unknown. Since the 1,3,4 isomer turns over very slowly, it may control long-term events and thus could play a role in cell growth. There are other growth factors such as insulin and epidermal growth factor (EGF), which apparently do not work through the inositol lipids but they may initiate ionic events similar to those just described for calcium-mobilizing receptors. The bifurcating signal pathway based on IP3/Ca2+ and DG/C-kinase provides an interesting framework within which to consider the mode of action of oncogenes.

Animals↗
PubMed1984

Actions of inositol phosphates on Ca2+ pools in guinea-pig hepatocytes.

In permeabilized hepatocytes, inositol 1,4,5-trisphosphate, inositol 2,4,5-trisphosphate and inositol 4,5-bisphosphate induced rapid release of Ca2+ from an ATP-dependent, non-mitochondrial vesicular pool, probably endoplasmic reticulum. The order of potency was inositol 1,4,5-trisphosphate greater than inositol 2,4,5-trisphosphate greater than inositol 4,5-bisphosphate. The Ca2+-releasing action of inositol 1,4,5-trisphosphate is not inhibited by high [Ca2+], nor is it dependent on [ATP] in the range of 50 microM-1.5 mM. These results suggest a role for inositol 1,4,5-trisphosphate as a second messenger in hormone-induced Ca2+ mobilisation, and that a specific receptor is involved in the Ca2+-release mechanism.

Adenosine Triphosphate↗
PubMed1984

Inositol 1,4,5-trisphosphate may be a signal for f-Met-Leu-Phe-induced intracellular Ca mobilisation in human leucocytes (HL-60 cells).

Permeabilised, dimethyl sulphoxide-differentiated HL-60 human myelomonocytic leukemia cells accumulate 45Ca in an ATP-dependent manner. The 45Ca is taken up by a pool thought to be a component of the endoplasmic reticulum. Inositol trisphosphate induced a rapid release of Ca from this pool, suggesting that this molecule which is formed in these cells in response to f-Met-Leu-Phe may play a role in agonist-induced Ca metabolism.

Adenosine Triphosphate↗
PubMed1984

Inositol 1,4,5-trisphosphate mobilizes intracellular Ca2+ from permeabilized insulin-secreting cells.

A possible role in secretory processes is proposed for inositol 1,4,5-triphosphate (IP3), based upon investigations of the Ca2+ steady state maintained by "leaky', insulin-secreting RINm5F cells. These cells had been treated with digitonin to permeabilize their plasma membranes and thereby ensure that only intracellular Ca2+ buffering mechanisms were active. When placed in a medium with a cation composition resembling that of the cytosol, cells rapidly took up Ca2+ as measured by a Ca2+-specific minielectrode. Two Ca2+ steady states were observed. A lower level of around 120nM required ATP-dependent Ca2+ uptake and was probably determined by the endoplasmic reticulum. The higher steady state (approx. 800 nM), seen only in the absence of ATP, was shown to be due to mitochondrial activity. IP3 specifically released Ca2+ accumulated in the ATP-dependent pool, but not from mitochondria, since Ca2+ release was demonstrated in the presence of the respiratory poison antimycin. The IP3-induced Ca2+ release was rapid, with 50% of the response being seen within 15s. The apparent Km was 0.5 microM and maximal concentrations of IP3 (2.5 microM) produced a peak Ca2+ release of 10 nmol/mg of cell protein, which was followed by re-uptake. A full Ca2+ response was seen if sequential pulses of 2.5 microM-IP3 were added at 20 min intervals, although there was a slight (less than 20%) attenuation if the intervening period was decreased to 10 min. These observations could be related to the rate of IP3 degradation which, in this system, corresponded to a 25% loss of added 32P label within 2 min, and a 75% loss within 20 min. The results suggest that IP3 might act as a link between metabolic, cationic and secretory events during the stimulation of insulin release.

Adenoma, Islet Cell↗
PubMed1984

Reduction of epidermal growth factor receptor affinity by heterologous ligands: evidence for a mechanism involving the breakdown of phosphoinositides and the activation of protein kinase C.

The tetradecapeptide bombesin converts epidermal growth factor (EGF) receptors on Swiss 3T3 cells from a high affinity state (KD = 9.8 X 10(-11)M) to a lower affinity state (KD = 1.8 X 10(-9)M). This conversion occurs when the cells are incubated with bombesin at 37 degrees C but not when incubated at 4 degrees C. Previously, a number of other (chemically unrelated) cell growth-promoting peptides and polypeptides have been shown to induce a similar indirect, temperature-dependent reduction of EGF receptor affinity. We have now demonstrated that hormones and growth factors which cross-regulate EGF receptor affinity in Swiss 3T3 cells have a common ability to stimulate the breakdown of phosphoinositides in these cells. We propose that the reduction of EGF receptor affinity is a consequence of the activation of protein kinase C by the diacylglycerol generated by this breakdown. In support of this proposal we have found that exogenously added diacylglycerol reduces the affinity of the Swiss 3T3 cell EGF receptor.

Animals↗
PubMed1984

Inositol trisphosphate formation and calcium mobilization in Swiss 3T3 cells in response to platelet-derived growth factor.

Swiss 3T3 cells incubated for 60 h with [3H]inositol incorporated radioactivity into phosphatidylinositol (PI) and the two polyphosphoinositides phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2). On stimulation with platelet-derived growth factor (PDGF) there were significant increases in the levels of inositol 1-phosphate (IP1), inositol 1,4-bisphosphate (IP2) and inositol 1,4,5-trisphosphate (IP3). The effect of PDGF and IP3 on Ca2+ mobilization was studied in both intact cells and in 'leaky' cells that had been permeabilized with saponin. In intact cells, PDGF stimulated the efflux of 45Ca2+, whereas IP3 had no effect. Conversely, IP3 stimulated 45Ca2+ efflux from 'leaky' cells, which were insensitive to PDGF. 'Leaky' cells, which accumulated 45Ca2+ to a steady state within 20 min, were found to release approx. 40% of the label within 1 min after addition of 10 microM-IP3. This stimulation of 45Ca2+ release by IP3 was reversible and was also dose-dependent, with a half-maximal effect at approx. 0.3 microM. It seems likely that an important action of PDGF on Swiss 3T3 cells is to stimulate the hydrolysis of PIP2 to form IP3 and diacylglycerol, both of which may function as second messengers. Our results indicate that IP3 mobilizes intracellular Ca2+, and we propose that diacylglycerol may act through C-kinase to activate the Na+/H+ antiport. By generating two second messengers, PDGF can simultaneously elevate the intracellular level of Ca2+ and alkalinize the cytoplasm by lowering the level of H+.

Animals↗
PubMed1984

Specificity of inositol trisphosphate-induced calcium release from permeabilized Swiss-mouse 3T3 cells.

Swiss-mouse 3T3 cells permeabilized with saponin were used to study the specificity of the inositol trisphosphate-induced release of 45Ca2+ from their intracellular stores. Inositol 1,4,5-trisphosphate was the most potent compound studied (dose giving half-maximal effect 0.3 microM). 45Ca2+ was also released by inositol 2,4,5-trisphosphate, glycerophosphoinositol 4,5-bisphosphate and inositol 4,5-bisphosphate, with doses giving half-maximal effect of respectively 1.6 microM, 1.6 microM and 20 microM, but not by inositol 1,4-bisphosphate (50 microM). These data suggest that the trans-vicinal phosphates on the 4- and 5-positions are essential for the Ca2+-mobilizing effect of inositol trisphosphate, and that in addition there is a requirement for a phosphate group on the opposite side of the molecule, with a preference for the 1-position.

Animals↗
PubMed1984

Relationship of polyphosphoinositide metabolism to the hormonal activation of the inset salivary gland by 5-hydroxytryptamine.

Incubation of the insect gland with [3H]inositol results in the incorporation of label into both phosphatidylinositol (PI) and the two polyphosphoinositides (PIP and PIP2). Upon stimulation with 5-HT the initial water-soluble metabolites released are inositol trisphosphate and inositol bisphosphate with no change in the level of inositol monophosphate, suggesting that the primary lipid substrate used by the receptor is one of the polyphosphoinositides (most likely PIP2) rather than PI. This conclusion was substantiated by showing that 5-HT was not able to release inositol or inositol monophosphate when the levels of the two polyphosphoinositides were reduced by lowering the level of ATP. The rate of breakdown of the polyphosphoinositides, as measured by the appearance of inositol phosphates, occurred with no apparent lag whereas the onset of the calcium-dependent change in transepithelial potential had a latency of approximately 1 sec. It is concluded that the primary action of 5-HT is to stimulate the hydrolysis of PIP2 into diacylglycerol and inositol trisphosphate. The latter may function as a second messenger to mobilize the calcium responsible for initiating some of the ionic events responsible for fluid secretion.

Adenosine Triphosphate↗