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Identifying novel roles in cell communication for disease-related proteins

D.J. Keating, Department of Human Physiology, Flinders University, Adelaide, SA 5001, Australia.

A major research interest of my group is in identifying previously unidentified roles in cell communication of proteins associated with neurodegeneration and human neurodegenerative disorders. We have recently identified the role of a chloride channel in regulating vesicle loading and release (Maritzen et al., 2008) and novel roles of Down syndrome-related proteins in regulating exocytosis (Keating et al., 2008; Yu et al., 2008). One of these proteins, known as Rcan1 (or Dscr1), is overexpressed in the brains of Down syndrome (DS) and Alzheimer’s disease (AD) individuals and is an endogenous inhibitor of the phosphatase calcineurin. Using mice which knock-out (KO) and transgenically overexpress (Tg) Rcan1 we find that Rcan1 regulates both the rate of exocytosis and vesicle fusion pore kinetics. The number of secretory events in chromaffin cells, a commonly used model of neuronal exocytosis, is decreased by 36% in mice transgenically overexpressing (Tg) Rcan1 (p<0.05, n=23) and 50% in mice with no Rcan1 (KO) expression (p<0.01, n=21). Rcan1 also positively influences the speed of vesicle pore opening and closing, resulting in lower levels of release from individual vesicles and more “kiss-and-run” type fusion in Rcan1 Tg cells. The reverse is seen in KO cells. These effects on fusion pore kinetics are due to chronic calcineurin inhibition by Rcan1. We have also investigated effects of Rcan1 on insulin-secreting beta cells in which calcineurin activity is critical (Heit et al., 2006). We find that pancreatic islet size, fasting blood glucose, glucose tolerance and the islet expression of genes important in β-cell survival, proliferation and insulin production are reduced in Rcan1 Tg mice. Rcan1 may therefore be an important new player in both neuronal and endocrine cell communication.

Maritzen T, Keating DJ, Neagoe I, Zdebik AA, Jentsch TJ. (2008) Role of the vesicular chloride transporter ClC-3 in neuroendocrine tissue. Journal of Neuroscience 28: 10587-98.

Keating DJ, Dubach D, Zanin MP, Yu Y, Martin K, Zhao YF, Chen C, Porta S, Arbonés ML, Mittaz L, Pritchard MA. (2008) DSCR1/RCAN1 regulates vesicle exocytosis and fusion pore kinetics: implications for Down syndrome and Alzheimer's disease. Human Molecular Genetics 17: 1020-30.

Yu Y, Chu PY, Bowser DN, Keating DJ, Dubach D, Harper I, Tkalcevic J, Finkelstein DI, Pritchard MA. (2008) Mice deficient for the chromosome 21 ortholog Itsn1 exhibit vesicle-trafficking abnormalities. Human Molecular Genetics 17: 3281-90.

Heit JJ, Apelqvist ÅA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK. (2006) Calcineurin/NFAT signalling regulates pancreatic β-cell growth and function. Nature 443: 345-9.