Michell R H. Inositol Phospholipids and Cell Surface Receptor Function
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This Week’s Citation Classic® DECEMBER 12, 1988 Michell R H. Inositol phospholipids and cell surface receptor function. Biochim. Biophys. Acta 415:81-147, 1975. [Department of Biochemistry. University of Birmingham. Englanill By the mid-i2~ 970s, it was clear that a rise in cvtoplas- AMP. We then recognised that it always coincided mic Ca concentration is an essential component or with receptor-activated mobilization of ~ within many of the responses of cells to hormones, neuro- stimulated cells. Once we were sure that receptor-ac- transmitters, and other extracellular stimuli, It then be- tivated inositol lipid hydrolysis was not caused by came clear that the same stimuli invariably enhance the mobilized Ca°~,there were only two possibili2~ - the turnover of inositol phospholipids. In this review ties: either inositol lipid hydrolysis and Ca mobi- article, I developed the idea, which has since been lization were unrelated2~ events or inositol lipid hy- proved correct, that receptor-triggered inositol lipid drolysis caused Ca mobilization. We elected the hydrolysis is a transmembrane signalling2~ reaction that latter as the more parsimonious and experimentally causes the mobilization of Ca within stimulated testable working model; and it was written up, sent cells. [The SCI~indicates that this paper has been to Nature, and rejected. At that time I fortunately cited in over 1755 publications.] had deferred my response to an invitation to write for Biochimica et Biophysica Acta’s Biomembrane Reviews. Coincidence of the new ideas with the im- pending arrival of a baby provoked me to write my p - review in the summer of 1974, so our idea first ap- peared in 1975 as the central conclusion of an ex- tensive review article rather than asa brief letter. Robert H. Michell In the next few years, general interesi1~ihepos- School of Biochemistry sibility that inositol lipid breakdown might be a wide- University of Birmingham spread and very important transmenibrane signalling Birmingham B15 2T1 reaction was relatively slow to develop, and this idea England was forcefully opposed by some workers until about 1983. However, by 1984 it had been shown that phosphatidylinositol 4,5-bisphosphate3 is the lipid hy- August 20, 1988 drolysed in response to stimulation (another idea that Nature didn’t want to publish and that first ap- peared in an invited review) and that thetwo prod- ucts of this reaction are second messengers: In the early 1960s, when I studied for my PhI) with 1,2-diacylglycerol4 activates Yasutomi Nishizuka’s J.N. film) Hawthorne,’ phospholipids were regarded protein kinase C, and inositol 1,4,5-trisphosphate as the greasy permeability barrier within biological links receptor activation to the release into5 the cy- membranes. However, the inositol phospholipids, tosol of (~2+from an intracellular stOre. The cel- which constitute oniy a small fraction of this mem- lular processes in whose control this system has since brane lipid, behaved in a unique2 manner; Mabel R. been implicated are legion; they include the fertil- Hokin and Lowell E. Hokin had shown that inositol ization of eggs, liberation of stored carbohydrate phospholipids, unlike other membrane lipids, show from the liver, and the switching on of immune cells enhanced metabolic turnover when many cells are by antigens. Moreover, it is now clear that other, pie- stimulated. Hawthorne passed on to me his fascina- viously unrecognised inositol lipids have specific cel- tion with this striking and enigmatic observation, so lular functions, including the anchoring of cell sur- I went to Harvard Medical School to participate in face proteins and possibly the generation of a medi- Manfred Karnovsky’s investigations ofthis response ator of insulin action, and that mammalian cells con- in phagocytizing neutrophils. tain substantial quantities of structurally diverse in- However, other studies intervened, and stimulated ositol phosphates whose functions are yet to be de- inositol lipid metabolism took a backseat until the termined.’ early 1970s, when Eduardo Lapetina, David Allan, As a result of my contributions to the recognition Lynne Jones, and I attacked it intensively. We real- that inositol lipids play a central role in cellular sig- ised that this response involved inositol lipid hydro- nalling processes, I have been elected to the Royal lysis and was implicated in diverse cellular responses Society and now hold a Royal Society Research Pro- to stimuli and also that it was triggered by a mecha- fessorship, and I have been awarded the CIBA Medal nism that did not involve the all-conquering cyclic of the Biochemical Society. I. Micheil R H & Hawthonie J N. The site of diphosphOinOsiude synthesis in rat liver. Btochem. Biopl,ys. Res. Commun. 21:333-8, 1965. (Cited 330 limes.) 2. Hokin M R & Hokin L E. Enzyme secrenon and the incorporation of P’ into phospholipids of pancreas slices. I. Biol. Chem. 203:967-77, 1953. (Cited 315 times since t955.) 3. Michell R H, Kirk Ci, Jones L M, Downes C P & Crime J A. The stimulation of inositol lipid metabolism that accompanies calcium mobilization in stimulated cells: defined characteristics and unanswered questions. Phil. Trans. Roy. Soc. London B 296:t23-37. 1981. (Cited 325 times.) 4. Nisbizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308:693-7. 1984. (Cited 2,070 times.) 5. Berndge M J & Irvine R F. tnositol tessphosphate. a novel second messenger in cellular signal transduction. Nature 312:315-21. 1984. (Cited 1,730 times.) ISee also: Bertidge Mi. Citation Classic. Current Contents/Clinical Medicine 16(31):t6, I August 1988 and CC/Life Sciences 31(31):t6. 1 August 1988.1 6. Bertidge M J & MlcheU It H, eds. lno~itollipids and transmembrane signalling. London: Royal Society, 1988. 436 p. 22 ~1988bylSl® CURRENT CONTENTS® ~= /.