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Second messengers are intracellular signaling molecules released by the cell in response to exposure to extracellular signaling molecules—the first messengers. (Intercellular signals, a non-local form of cell signaling, encompassing both first messengers and second messengers, are classified as autocrine, juxtacrine, paracrine, and endocrine system depending on the range of the signal.) Second messengers trigger physiological changes at cellular level such as proliferation, differentiation, migration, survival, apoptosis and depolarization.
They are one of the triggers of intracellular signal transduction cascades. (2001). 9780470016176, John Wiley & Sons Ltd. ISBN 9780470016176
Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol triphosphate, diacylglycerol, and calcium. (2017). 9780323341264, Elsevier Inc. ISBN 9780323341264 First messengers are extracellular factors, often or , such as epinephrine, growth hormone, and serotonin. Because and neurotransmitters typically are biochemically hydrophile molecules, these first messengers may not physically cross the Lipid bilayer to initiate changes within the cell directly—unlike , which usually do. This functional limitation requires the cell to have 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, Ras GTPase signals link with the mitogen activated protein kinase (MAPK) cascade to amplify the allosteric activation of proliferative transcription factors such as Myc and CREB.
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.
Secondary messenger systems can be synthesized and activated by enzymes, for example, the cyclases that synthesize cyclic nucleotides, or by opening of to allow influx of metal ions, for example Ca2+ signaling. These small molecules bind and activate protein kinases, ion channels, and other proteins, thus continuing the signaling cascade.
These intracellular messengers have some properties in common:
In most cases, a ligand binds to a cell surface receptor. The binding of a ligand to the receptor causes a conformation change in the receptor. This conformation change can affect the activity of the receptor and result in the production of active second messengers.
In the case of G protein-coupled receptors, the conformation change exposes a binding site for a G-protein. The G-protein (named for the GDP and GTP molecules that bind to it) is bound to the inner membrane of the cell and consists of three subunits: alpha, beta and gamma. The G-protein is known as the "transducer."
When the G-protein binds with the receptor, it becomes able to exchange a GDP (guanosine diphosphate) molecule on its alpha subunit for a GTP (guanosine triphosphate) molecule. Once this exchange takes place, the alpha subunit of the G-protein transducer breaks free from the beta and gamma subunits, all parts remaining membrane-bound. The alpha subunit, now free to move along the inner membrane, eventually contacts another cell surface receptor - the "primary effector."
The primary effector then has an action, which creates a signal that can diffuse within the cell. This signal is called the "second (or secondary) messenger." The secondary messenger may then activate a "secondary effector" whose effects depend on the particular secondary messenger system.
Calcium ions are one type of second messengers and are responsible for many important physiological functions including muscle contraction, Fertilisation, and neurotransmitter release. The ions are normally bound or stored in intracellular components (such as the endoplasmic reticulum(ER)) and can be released during signal transduction. The enzyme phospholipase C produces diglyceride and inositol trisphosphate, which increases calcium ion permeability into the membrane. Active G-protein open up calcium channels to let calcium ions enter the plasma membrane. The other product of phospholipase C, diacylglycerol, activates protein kinase C, which assists in the activation of cAMP (another second messenger).
Binding of a primary messenger to these receptors results in conformational change of the receptor. The α subunit, with the help of guanine nucleotide exchange factors (GEFS), releases GDP, and binds GTP, resulting in the dissociation of the subunit and subsequent activation. The activated α subunit activates phospholipase C, which hydrolyzes membrane bound phosphatidylinositol 4,5-bisphosphate (PIP2), resulting in the formation of secondary messengers diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). IP3 binds to calcium pumps on ER, transporting Ca2+, another second messenger, into the cytoplasm. (2025). 9780878937424, Sinauer Associates. ISBN 9780878937424 Ca2+ ultimately binds to many proteins, activating a cascade of enzymatic pathways.
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