Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine (adrenaline), growth factors, and others, and cause some kind of change in the activity of the cell. They greatly amplify the strength of the signal.[1][2] Secondary messengers are a component of signal transduction cascades.

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.[3] The mechanisms were worked out in detail[4][5] by Martin Rodbell and Alfred G. Gilman, who won the 1994 Nobel prize.

Secondary messenger systems can be synthesized and activated by enzymes, like the cyclases that synthesize cyclic nucleotides, or by opening of ion channels to allow influx of metal ions, like Ca2+ signaling. These small molecules bind and activate protein kinases, ion channels, and other proteins, thus continuing the signaling cascade.

Types of secondary messenger molecules

There are three basic types of secondary messenger molecules:

These intracellular messengers have some properties in common:

  • They can be synthesized/released and broken down again in specific reactions by enzymes or ion channels.
  • 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.

Common mechanisms of secondary messenger systems

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 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 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, fertilization, and neurotransmitter release. 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 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).


cAMP System Phosphoinositol system Arachidonic acid system cGMP System Tyrosine kinase system
Epinephrine (α2, β1, β2)
Acetylcholine (M2)
Epinephrine (α1)
Acetylcholine (M1, M3)
Histamine (Histamine receptor) - -
ACTH, ANP, CRH, CT, FSH, Glucagon, hCG, LH, MSH, PTH, TSH AGT, GnRH, GHRH, Oxytocin, TRH - ANP, Nitric oxide INS, IGF, PDGF
Transducer Gs (β1, β2), Gi (α2, M2) Gq Unknown G-protein - -
Primary effector Adenylyl cyclase Phospholipase C Phospholipase A guanylate cyclase receptor tyrosine kinase
Secondary messenger cAMP (cyclic adenosine monophosphate) IP3 (inositol 1,4,5 trisphosphate) and DAG (Diacylglycerol), both from PIP2 Arachidonic acid cGMP protein phosphatase
Secondary effector protein kinase A Ca++ release (see calcium-binding protein) and PKC (protein kinase C) 5-Lipoxygenase, 12-Lipoxygenase, cycloxygenase protein kinase G -


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