Berridge had been studying
cell signaling when he was at
Case Western Reserve University, where he received advice from Theodore W. Rall, co-discoverer of the
second messenger cyclic AMP with
Earl Wilbur Sutherland Jr., who had also worked at Case Western Reserve. Working on the
salivary glands of a
blow fly species, Berridge showed cyclic AMP produced the same
physiological effect as
serotonin, dramatically increasing
saliva secretion. The idea of second messenger was new at the time, and his finding supported cyclic AMP as a second messenger of serotonin. He continued studying cyclic AMP after returning to the
University of Cambridge, and conducted experiments to study how serotonin and cyclic AMP affected the movement of
ions, as ion concentration difference across the salivary gland
epithelium controlled the movement of water across the epithelium through
osmosis. Berridge measured the
difference in electric potential across the epithelium since ions are
charged. Berridge suspected
calcium ions (Ca2+) could explain the distinct electrical but similar physiological effects of serotonin and cyclic AMP. In 1971,
Howard Rasmussen, one of the first researchers to recognise the role of Ca2+ as a second messenger, was on a
sabbatical at Cambridge. Later, he confirmed that serotonin activated two distinct receptor system, one through cyclic AMP and the other through Ca2+. Berridge then wanted to identify the connection between
cell surface receptor activation and the release of intracellular Ca2+ from storage. He was inspired by a review article by Robert H. Michell in 1975, which proposed receptor activation caused the breakdown of
phosphatidylinositol, which in turn opened
Ca2+ channels on the
cell membrane to allowing Ca2+ influx into cells. He hypothesised phosphatidylinositol was
hydrolysed into a form of
inositol phosphate and
diglyceride (DAG), and the former was eventually broken down into
inositol. He applied
lithium ions to blow fly salivary glands to inhibit the conversion of inositol phosphate to inositol. With help from
Rex Malcolm Chaplin Dawson, who was studying inositol at the
Babraham Institute near Cambridge, Berridge found that phosphatidylinositol was hydrolysed into
IP3 and DAG. Later the same year, he confirmed IP3 released Ca2+ from the intracellular storage, which he identified as the
endoplasmic reticulum. This report, together with
Yasutomi Nishizuka's discovery that DAG was a
second messenger in its own right and could activate
protein kinase C, marked the start of the field of
calcium signaling. == Awards and honours ==