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Rab3 Small GTP—Binding Proteins: Regulation by Calcium/Calmodulin

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Signal Transduction and Cardiac Hypertrophy

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 7))

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Summary

Rab proteins, forming a subfamily of 52 predominantly membrane-bound, low molecular weight GTP-binding proteins (G-proteins) of the Ras superfamily, are involved in vesicle traffic between intracellular organelles, endocytosis and exocytosis, and may be regulated by calcium (Ca2 +) and/or calmodulin (CaM). Rab3A and Rab3B bind CaM, and both RabGDP-dissociation inhibitor (RabGDI) and CaM cause dissociation of Rab3A from membranes, to form soluble cytoplasmic Rab/CaM or Rab/RabGDI complexes. This shuttling is intimately connected with the cycling of Rab between the active GTP-bound (at organelle membranes) and inactive GDP-bound (cytosolic) state, enabling Rab to function as molecular switches in the regulation of various cell functions. Rab3A inhibits, while Rab3B promotes, Ca2+-dependent exocytosis. Recent work has demonstrated that Rab3’s effects on exocytosis are regulated by CaM, in that CaM may enhance the dissociation of Rab by RabGDI in a Ca2+-dependent manner. RabGDI binds only to inactive Rab, while CaM binds with much higher affinity to active Rab3A. Ca2+/CaM can induce GDP to GTP exchange on Rab if RabGDI is not bound. It is proposed that increased intracellular Ca2+ concentration causes RabGDI to be replaced by CaM on Rab-GDP, allowing CaM to exert its effects through an activated Rab3. At high intracellular Ca2+ levels, the Rab3-GTP/CaM complex may predominate over the Rab3-GDP/RabGDI complex. Competitive rebinding of RabGDI to Rab-GDP, but not to Rab-GTP, would cause release of CaM and reversal of its effects. Thus, Ca2+ and CaM appear to be important regulators of Rab3 function. It is important to elucidate the exact mechanisms of such interactions, and which intracellular pathways are involved.

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Authors and Affiliations

  1. Departments of Oral Biology, University of Manitoba, 780 Bannatyne Avenue, R3E 0W3, Winnipeg, Manitoba, Canada

    Ranjinder S. Sidhu, Richard R. Clough & Dr. Rajinder P. Bhullar

  2. Biochemistry & Medical Genetics, University of Manitoba, 780 Bannatyne Avenue, R3E 0W3, Winnipeg, Manitoba, Canada

    Dr. Rajinder P. Bhullar

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  1. Ranjinder S. Sidhu
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Correspondence to Rajinder P. Bhullar .

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  1. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla PhD, MD (Hon), DSc (Hon) (Distinguished Professor and Director), Larry V. Hryshko PhD (Associate Professor), Elissavet Kardami PhD (Professor) & Pawan K. Singal PhD, DSc (Professor) (Distinguished Professor and Director),  (Associate Professor),  (Professor) &  (Professor)

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Sidhu, R.S., Clough, R.R., Bhullar, R.P. (2003). Rab3 Small GTP—Binding Proteins: Regulation by Calcium/Calmodulin. In: Dhalla, N.S., Hryshko, L.V., Kardami, E., Singal, P.K. (eds) Signal Transduction and Cardiac Hypertrophy. Progress in Experimental Cardiology, vol 7. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0347-7_13

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  • DOI: https://doi.org/10.1007/978-1-4615-0347-7_13

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