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In cell physiology, a secondary messenger system (also known as a second messenger system) is a method of cellular signaling, whereby the signaling molecule does not enter the cell but rather utilizes a cascade of events that transduces the signal into a cellular change. Secondary messengers are a component of signal transduction cascades.

Secondary messenger systems utilize receptors on the surface of the plasma membrane, which are generally coupled to a kinase on the interior surface of the membrane. The kinase then phosphorylates another molecule (frequently cAMP), which carries out another action.

Secondary messengers are associated with many hormones, but they are not used by steroid hormone receptors or ligand-gated ion channels.

There are three basic types of secondary messenger molecules:

• Hydrophobic molecules: water-insoluble molecules, like diacylglycerol, InsP₃, and phosphatidylinositols, which are membrane-associated and diffuse from the plasma membrane into the juxtamembrane space where they can reach and regulate membrane-associated effector proteins
• Hydrophilic molecules: water-soluble molecules, like cAMP, cGMP, and Ca²⁺, that are located within the cytosol
• Gases: nitric oxide (NO) and carbon monoxide (CO), which can diffuse both through cytosol and across cellular membranes.

These intracellular messengers have some properties in common:

• They can be synthesized/released and broken down again in specific reactions by enzymes.
• Some (like Ca²⁺) can be stored in special organelles and quickly released when needed.
• Their production/release and destruction can be localized, enabling the cell to limit space and time of signal activity.

There are several different secondary messenger systems (cAMP system, phosphoinositol system, and arachidonic acid system), but they all are quite similar in overall mechanism, though the substances involved in those mechanisms and effects are different.

In all of these cases a neurotransmitter binds to a membrane-spanning receptor protein molecule. The binding of the neurotransmitter to the receptor changes the receptor and causes it to expose a binding site for a G-protein. The G-protein (named for the GDP and GTP molecules that binds 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 to 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 membrane-bound protein - 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 "secondary messenger." (The neurotransmitter is the first messenger.) The secondary messenger may then activate a "secondary effector" whose effects depend on the particular secondary messenger system.

Calcium ions are responsible for many important physiological functions, such as in muscle contraction. It is normally bound to intracellular components even though a secondary messenger is a plasma membrane receptor. Calcium regulates the protein calmodulin, and, when bound to calmodulin, it produces an alpha helical structure. This is also important in muscle contraction. The enzyme phospholipase C produces diacylglycerol and inositol triphosphate, 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).

• MeSH Second+Messenger+Systems
• Kimball, J. Second messengers. Retrieved on February 10, 2006.