What are second messengers? Signals received by receptors at the cell surface or, in some cases, within the cell are often relayed throughout the cell via generation of small, rapidly diffusing molecules referred to as second messengers. These second messengers broadcast the initial signal (the “first message”) that occurs when a ligand binds to a specific cellular receptor; ligand binding alters the protein conformation of the receptor such that it stimulates nearby effector proteins that catalyze the production or, in the case of ions, release or influx of the second messenger. The second messenger then diffuses rapidly to protein targets elsewhere within the cell, altering the activities as a response to the new information received by the receptor.
Three classic second messenger pathways are:
(1) activation of adenylyl cyclase by G-protein-coupled receptors (GPCRs) to generate the cyclic nucleotide second messenger 3′-5′-cyclic adenosine monophosphate (cAMP);
(2) stimulation of phosphoinositide 3-kinase (PI3K) by growth factor receptors to generate the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3); and
(3) activation of phospholipase C by GPCRs to generate the two second messengers membrane-bound messenger diacylglycerol (DAG) and soluble messenger inositol 1,4,5-trisphosphate (IP3), which binds to receptors on subcellular organelles to release calcium into the cytosol.
The activation of multiple effector pathways by a single plasma membrane receptor and the production of multiple second messengers by each effector can generate a high degree of amplification in signal transduction, and stimulate diverse, pleiotropic, responses depending on the cell type.
Second messengers fall into four major classes:
(1) cyclic nucleotides, such as cAMP and other soluble molecules that signal within the cytosol;
(2) lipid messengers that signal within cell membranes;
(3) ions that signal within and between cellular compartments;
(4) gases and free radicals that can signal throughout the cell and even to neighboring cells.
Second messengers from each of these classes bind to specific protein targets, altering their activity to relay downstream signals. In many cases, these targets are enzymes whose catalytic activity ismodified by direct binding of the second messengers. The activation of multiple target enzymes by a single second messenger molecule further amplifies the signal.
Newton A C, et al. Second messengers[J]. Cold Spring Harbor perspectives in biology, 2016, 8(8): a005926.