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Professor John Forte

John Forte died peacefully on 19 November 2012 at his home surrounded by family following prolonged illness with leukaemia. He is survived by his loving wife of 51 years, Trudy; his daughters, Michele Ramos (partner Marcelio Ramos) and Susan McElhany (partner Clay McElhany); his son John (partner Nicole); and his grandchildren, Marcel, Gaetano, Giovanna, Fiona, Peter, Rafael and Stuart. John spent his childhood in Philadelphia, PA, USA. He attended Valley Forge Military Academy and College and completed his undergraduate degree at Johns Hopkins University. He played football and was also captain of the fencing team at Johns Hopkins, earning National Collegiate Athletic Association honours for sabre fencing. He earned his PhD from the University of Pennsylvania.

In 1965, John and Trudy moved to Berkeley, CA, and he began his tenure as a Professor of Physiology at the University of California, Berkeley (UCB). He received many honours for research and excellence in teaching during his 47-year career at UCB. His contributions describing the mechanism of the hydrogen ion pump of the stomach helped to produce pharmacological treatments for ulcers. He served on editorial boards of numerous scientific journals. Some of the honours he received were a Guggenheim Fellowship, Honorary Member of the British Society of Gastroenterology, William Beaumont Prize in Gastroenterology, Distinguished Lecturer of the American Physiological Society, Sheikh Hamdan Bin Rashid Al Maktoum Award for Medical Sciences and Distinguished Achievement Award American Gastroenterology Association.

John was a devoted and active member of the St Mary Magdalen Parish in Berkeley. A supporter of local performing arts, he enjoyed lending his baritone voice to the UCB Monks Faculty Choir and church choir. He expressed his creative talents through carvings and furniture woodworking. He enjoyed time spent with family and friends.

Highlights of Forte’s research on the gastric proton pump

Discovery and characterization of H,K-ATPase

Professor Forte’s work led to the discovery of the gastric proton pump as the K+-stimulated ATPase, first in amphibians then in mammals.13 This represented a whole new concept in describing the origin of gastric acid, completely distinct from all previous theories and proposals.

His work led to the biochemical and biophysical characterization of the gastric proton pump, now also known as H,K-ATPase.47 This research later led to the development of the pump-leak model for isolated gastric vesicles, which described the biophysics of proton transport in terms of a H/K exchange pump and diffusive leaks for K+ and Cl.8

Professor Forte helped formulate the membrane recycling hypothesis of HCl secretion,911 representing the first system in which the recruitment and turnover of membrane pumps and transporters was proposed as a mechanism for up- and down-regulation.

He reconstituted the complete functional gastric proton pump. Morphological and biochemical evidence established the stimulation-associated recruitment and recycling of the proton pump, including functional changes in membrane transport proteins.1215 The integrated hypothesis accounted for the regulation of HCl secretion as well as the solution for the electrophysiological ‘conundrum’ of how an electroneutral pump can account for electrogenic H+ and Cl transport in vivo.16

His work also showed how the gastric proton pump was a heterodimer consisting of α- and β-subunits,17,18 and demonstrated structural and functional parallelism among the family of P-type cation exchange pumps, e.g. Na,K-ATPase.19

Landmarks for the prevention of, and non-invasive therapy for, gastrointestinal disorders

In 1981, the gastric H,K-ATPase was defined as the target for developing specific antisecretory drugs, such as omeprazole and other substituted benzimidazoles.20 In the mid-1980s, omeprazole underwent clinical trials,21 and was then joined by several other analogues to create a therapy widely used to treat peptic ulcer disease, heartburn, gastro-oesophageal reflux disease and Zollinger–Ellison syndrome. These drugs are used worldwide to relieve, literally, millions of people from the pain and suffering associated with gastric hypersecretion; their use has virtually eliminated the need for gastric surgery (except for gastric carcinoma) or vagotomy, which were very common prior to 1990.

References

1. 

Forte JG, Forte GM, Saltman PD. K+-stimulated phosphatase of microsomes from gastric mucosa. J Cell Physiol 1967; 69:293–304. http://dx.doi.org/10.1002/jcp.1040690305

2. 

Ganser AL, Forte JG. K+-stimulated ATPase in purified microsomes of bullfrog oxyntic cells. Biochim Biophys Acta 1973; 307:169–80. http://dx.doi.org/10.1016/0005-2736(73)90035-7

3. 

Forte JG, Ganser A, Beesley R, Forte TM. Unique enzymes of purified microsomes from pig fundic mucosa: K+-stimulated ATPase and K+-stimulated pNPPase. Gastroenterology 1975; 69:175–89.

4. 

Tanisawa AS, Forte JG. Phosphorylated intermediate of microsomal ATPase from rabbit gastric mucosa. Arch Biochem Biophys 1971; 147:165–75. http://dx.doi.org/10.1016/0003-9861(71)90323-7

5. 

Forte JG, Ganser AL, Tanisawa AS. The K+-stimulated ATPase system of microsomal membranes from gastric oxyntic cells. Ann NY Acad Sci 1974; 242:255–67. http://dx.doi.org/10.1111/j.1749-6632.1974.tb19095.x

6. 

Ray TK, Forte JG. Studies on the phosphorylated intermediates of a K+-stimulated ATPase from rabbit gastric mucosa. Biochim Biophys Acta 1976; 443:451–67. http://dx.doi.org/10.1016/0005-2736(76)90465-X

7. 

Lee HC, Forte JG. A study of H+ transport in gastric microsomal vesicles using fluorescent probes. Biochim Biophys Acta 1978; 508:339–56. http://dx.doi.org/10.1016/0005-2736(78)90336-X

8. 

Lee HC, Breitbart H, Berman M, Forte JG. Potassium-stimulated ATPase activity and H+ transport in gastric microsomal vesicles. Biochim Biophys Acta 1979; 553:107–31. http://dx.doi.org/10.1016/0005-2736(79)90034-8

9. 

Kasbekar DK, Forte GM, Forte JG. Phospholipid turnover and ultrastructural changes in resting and secreting bullfrog gastric mucosa. Biochim Biophys Acta 1968; 163:1–13. http://dx.doi.org/10.1016/0005-2736(68)90026-6

10. 

Forte TM, Machen TE, Forte JG. Ultrastructural changes in oxyntic cells associated with secretory function: a membrane recycling hypothesis. Gastroenterology 1977; 73:941–55.

11. 

Forte JG, Black JA, Forte TM, Machen TE, Wolosin JM. Ultrastructural changes related to functional activity in gastric oxyntic cells. Am J Physiol 1981; 241:G349–58.

12. 

Wolosin JM, Forte JG. Changes in membrane environment of H,K-ATPase following stimulation of the gastric oxyntic cell. J Biol Chem 1981; 256:3149–52.

13. 

Wolosin JM, Forte JG. Functional differences between K+-ATPase rich membranes isolated from resting and stimulated rabbit fundic mucosa. FEBS Lett 1981; 125:208–11. http://dx.doi.org/10.1016/0014-5793(81)80720-X

14. 

Wolosin JM, Forte JG. Stimulation of oxyntic cell triggers K+ and Cl conductances in apical (H++K+)-ATPase membrane. Am J Physiol 1984; 246:C537–45.

15. 

Hirst BH, Forte JG. Redistribution and characterization of (H++ K+)-ATPase membranes from resting and stimulated gastric parietal cells. Biochem J 1985; 231:641–9.

16. 

Reenstra WW, Forte JG. Characterization of K+ and Cl conductances in apical membrane vesicles from stimulated rabbit oxyntic cells. Am J Physiol 1990; 259:G850–8.

17. 

Okamoto CT, Karpilow JM, Smolka A, Forte JG. Isolation and characterization of gastric microsomal glycoproteins. Evidence for a glycosylated β-subunit of the H,K-ATPase. Biochim Biophys Acta 1990; 1037:360–72. http://dx.doi.org/10.1016/0167-4838(90)90038-H

18. 

Canfield VA, Okamoto CT, Chow D, et al. Cloning of the H,K-ATPase β subunit. Tissue-specific expression, chromosomal assignment, and relationship to Na,K-ATPase β subunits. J Biol Chem 1990; 265:19878–84.

19. 

Chow DC, Forte JG. Functional significance of the β-subunit for heterodimeric P-type ATPases. J Exp Biol 1995; 198:1–17.

20. 

Fellenius E, Berglindh T, Sachs G, et al. Substituted benzimidazoles inhibit gastric acid secretion by blocking (H++K+)ATPase. Nature 1981; 290:159–61. http://dx.doi.org/10.1038/290159a0

21. 

Walan A. Clinical perspectives of drugs inhibiting acid secretion – H+K+-ATPase inhibitors. Scand J Gastroenterol Suppl 1986; 125:50–4. http://dx.doi.org/10.3109/00365528609093817




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