The second messenger is an intracellular signaling molecule released by the cell in response to exposure to an extracellular signaling molecule-the first messenger. (Intracellular signals, non-local forms or cellular signaling, including first messengers and second messengers, classified as adjacent secretion, paracrine and endocrine according to the range of signals.) Second messengers induce physiological changes at the cellular level, Such as proliferation, differentiation, migration, survival and apoptosis. They are one of the triggers for the intracellular signal transduction cascade. Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol triphosphate, diacylglycerol and calcium. The first messenger is an extracellular factor, usually a hormone or neurotransmitter (Figure 1) such as adrenaline, growth hormone and serotonin. Because peptide hormones and neurotransmitters are typically biochemically hydrophilic molecules, these first messengers may not physically cross the phospholipid bilayer to directly trigger intracellular changes-unlike the usual steroid hormones. This functional restriction requires the cell to design a signal transduction mechanism to transduce the first messenger into a second messenger so that extracellular signals can propagate within the cell. An important feature of the second messenger signaling system is that the second messenger can be connected downstream to the polycyclic kinase cascade to greatly amplify the intensity of the original first messenger signal.
Figure 1. Structure of a typical chemical synapse.
Types of second messenger molecules
Hydrophobic molecules: Water-insoluble molecules, such as diacylglycerols and phosphatidylinositols, which bind to membranes and diffuse from the plasma membrane to the membrane space where they can reach and regulate membrane-associated effector proteins.
Hydrophilic molecules: water-soluble molecules, such as cAMP, cGMP, IP3, and Ca2+, that are located within the cytosol.
Gases: nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) which can diffuse both through cytosol and across cellular membranes.
These intracellular messengers have some common characteristics:
They can be synthesized/released in a specific reaction by an enzyme or an ion channel and decomposed again.
Some (such as Ca2+) can be stored in special organelles and released quickly when needed.
Their production/release and destruction can be localized, allowing cells to limit the space and time of signal activity.
|cAMP System||Phosphoinositol system||Arachidonic acid system||cGMP System||Tyrosine kinase system|
|Second messenger||cAMP (cyclic adenosine monophosphate)||IP3; DAG; Ca2+||Arachidonic acid||cGMP||Ras.GTP (Small G Protein)|
Second Messengers in the Phosphoinositol Signaling Pathway
IP3, DAG and Ca2+ are the second messengers in the phosphoinositide pathway. This pathway begins with the binding of extracellular major messengers such as epinephrine, acetylcholine and the hormones AGT, GnRH, oxytocin and TRH to their respective receptors. Epinephrine binds to the α1 GTPase protein-coupled receptor (GPCR), which binds to M1 and M2 GPCR.
The primary messenger binds to these receptors resulting in a conformational change in the receptor. The alpha subunit releases GDP with the help of guanine nucleotide exchange factor (GEFS) and binds to GTP, resulting in dissociation and subsequent activation of the subunit. Activated alpha subunit activates phospholipase C, phosphatase C hydrolyzes membrane-bound phosphatidylinositol-4,4-diphosphate (PIP2), resulting in the formation of second messenger diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3). IP3 binds to the calcium pump on the endoplasmic reticulum membrane and transports another second messenger, Ca2+, into the cytoplasm. Ca2+ eventually binds to many proteins and activates a range of enzymatic pathways.
Figure 2. The Phosphoinosital signaling pathway.
1. Wedegaertner PB.; et al. Lipid modifications of trimeric G proteins. The Journal of Biological Chemistry. 1995,270 (2): 503-506.
2. Hughes AR.; et al. Inositol phosphate formation and its relationship to calcium signaling. Environmental Health Perspectives. 1990, 84: 141-147.