<P> Second messengers are intracellular signaling molecules released by the cell to trigger physiological changes such as proliferation, differentiation, migration, survival, and apoptosis . Secondary messengers are therefore one of the initiating components of intracellular signal transduction cascades . Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol trisphosphate, diacylglycerol, and calcium . The cell releases second messenger molecules in response to exposure to extracellular signaling molecules--the first messengers . First messengers are extracellular factors, often hormones or neurotransmitters, such as epinephrine, growth hormone, and serotonin . Because peptide hormones and neurotransmitters typically are biochemically hydrophilic molecules, these first messengers may not physically cross the phospholipid bilayer to initiate changes within the cell directly--unlike steroid hormones, which usually do . This functional limitation necessitates the cell to devise signal transduction mechanisms to transduce first messenger into second messengers, so that the extracellular signal may be propagated intracellularly . An important feature of the second messenger signaling system is that second messengers may be coupled downstream to multi-cyclic kinase cascades to greatly amplify the strength of the original first messenger signal . For example, RasGTP signals link with the Mitogen Activated Protein Kinase (MAPK) cascade to amplify the allosteric activation of proliferative transcription factors such as Myc and CREB . </P> <P> Earl Wilbur Sutherland, Jr., discovered second messengers, for which he won the 1971 Nobel Prize in Physiology or Medicine . Sutherland saw that epinephrine would stimulate the liver to convert glycogen to glucose (sugar) in liver cells, but epinephrine alone would not convert glycogen to glucose . He found that epinephrine had to trigger a second messenger, cyclic AMP, for the liver to convert glycogen to glucose . The mechanisms were worked out in detail by Martin Rodbell and Alfred G. Gilman, who won the 1994 Nobel Prize . </P>

The link between the first messenger and the second messenger is
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