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In preparing an invited presentation for the 6th FASEB conference on “The biology of calpains in health and disease” I found that we were marking the 50th anniversary of the July 1963 submission of Gordon Guroff’s paper from the Laboratory for Clinical Biochemistry at the National Heart Institute of NIH published in J Biol Chem 1964, vol 239, 149-155. Based on an observation (also published in 1964) future Nobel Laureate Edwin G Krebs and RB Huston reported a calcium stimulated proteolytic ‘factor’ from cardiac muscle tissue in Biochemistry 1968, vol 7, 2116-­2122.

These reports are generally agreed to be our initial encounters with what became known as calpain-2. Not surprisingly these early investigations used excitable tissues, nerve and muscle where early physiological evidence documented the importance of calcium ions. Guroff asked What are the proteolytic enzymes in brain? And How do they relate to other known proteases? Kreb’s group hypothesized that the factor responsible for calcium activation of skeletal muscle phosphorylase kinase – might be a calcium activated protease. They called the kinase activating factor “KAF” and concluded that “KAF is a proteolytic enzyme casts great doubt as to its physiological role…” The bias that proteolysis, an irreversible event for any given target, would not be a significant physiological regulatory mechanism persisted from the late 60’s until ~1990.

I was asked to prepare a ‘postable’ version of calpain history for this calpain.org, a site initiated and maintained by Dr. Hiro Sorimachi, his laboratory and colleagues (Tokyo, JP). My approach is to lay out some ‘bones’ for three core threads of calpain investigations:
1) Biochemistry and Molecular Biology: protein isolation and characterization; cloning of the ‘family founder’ isoforms‐ calpain-1 and calpain-2 and discovery of the rest of the family; recombinant expression that fueled structural solutions and insights and a summary of tools/reagents developed and shared through these efforts of basic scientific inquiry.
2) Genetics and Evolution: Developing and lessons from targeted deletion of calpain genes in mice; Insights from evolution: Insights from human genetics.
3) Physiology and Pathology: Muscle (protein turnover, development and relevance to meat science and Muscular dystrophies); Nerve (mechanisms of synaptic plasticity and memory‐ neurodegenerative processes and diseases‐ cataract formation); Signal transduction pathways related to cellular adhesion and migration; Mechanisms of Pathogenesis.

This initial posting should be viewed as a ‘work in progress’‐ as I hope that some of the early ‘players’ will provide additional information and insight into areas that I have inadequately presented. We aim to provide annual updates as long as interest and opportunity suggest those updates, corrections and annotations are useful.

Dorothy E Croall, PhD.
Professor of Biochemistry , University of Maine
Orono, ME 04469-­‐5735 USA
**a Calpain ‘addict’ since 1982

Section 1: Biochemistry and Molecular Biology
Section 2: Genetics and Evolution New!!
Section 3: Physiology and Pathology
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