<P> Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules--the first messengers . Second messengers trigger physiological changes such as proliferation, differentiation, migration, survival, and apoptosis . They are one of the triggers of intracellular signal transduction cascades . </P> <P> Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol trisphosphate, diacylglycerol, and calcium . 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> <P> Secondary messenger systems can be synthesized and activated by enzymes, for example, the cyclases that synthesize cyclic nucleotides, or by opening of ion channels to allow influx of metal ions, for example Ca signaling . These small molecules bind and activate protein kinases, ion channels, and other proteins, thus continuing the signaling cascade . </P>

Where are second messengers located in the cell