Second messenger system

Second messengersareintracellular signalingmolecules released by the cell in response to exposure to extracellular signaling molecules—thefirst messengers.(Intercellular signals, a non-local form ofcell signaling,encompassing both first messengers and second messengers, are classified asautocrine,juxtacrine,paracrine,andendocrinedepending on the range of the signal.) Second messengers trigger physiological changes at cellular level such asproliferation,differentiation,migration, survival,apoptosisanddepolarization.

They are one of the triggers of intracellularsignal transductioncascades.

Examples of second messenger molecules includecyclic AMP,cyclic GMP,inositol triphosphate,diacylglycerol,andcalcium.First messengers are extracellular factors, oftenhormonesorneurotransmitters,such asepinephrine,growth hormone,andserotonin.Becausepeptide hormonesand neurotransmitters typically are biochemicallyhydrophilicmolecules, these first messengers may not physically cross thephospholipid bilayerto initiate changes within the cell directly—unlikesteroid hormones,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,RasGTPsignals link with themitogen activated protein kinase(MAPK) cascade to amplify the allosteric activation of proliferative transcription factors such asMycandCREB.

Earl Wilbur Sutherland Jr.,discovered second messengers, for which he won the 1971Nobel Prize in Physiology or Medicine.Sutherland saw thatepinephrinewould stimulate the liver to convertglycogentoglucose(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 byMartin RodbellandAlfred G. Gilman,who won the 1994 Nobel Prize.

Secondary messenger systems can be synthesized and activated by enzymes, for example, the cyclases that synthesizecyclic nucleotides,or by opening ofion channelsto allow influx of metal ions, for exampleCa²⁺signaling.These small molecules bind and activate protein kinases, ion channels, and other proteins, thus continuing the signaling cascade.

Types of second messenger molecules

There are three basic types of secondary messenger molecules:

• Hydrophobicmolecules:water-insoluble molecules such asdiacylglycerol,andphosphatidylinositols,which are membrane-associated and diffuse from theplasma membraneinto theintermembrane spacewhere they can reach and regulate membrane-associatedeffector proteins.
• Hydrophilicmolecules:water-soluble molecules, such ascAMP,cGMP,IP₃,andCa²⁺,that are located within thecytosol.
• Gases:nitric oxide (NO),carbon monoxide (CO)andhydrogen sulfide (H₂S)which can diffuse both through cytosol and acrosscellular membranes.

These intracellular messengers have some properties in common:

• They can be synthesized/released and broken down again in specific reactions byenzymesor ion channels.
• Some (such as Ca²⁺) can be stored in specialorganellesand quickly released when needed.
• Their production/release and destruction can belocalized,enabling the cell to limit space and time of signal activity.

Common mechanisms of second messenger systems

General Schematic of Second Messenger Mechanism

There are several different secondary messenger systems (cAMPsystem,phosphoinositolsystem, andarachidonic acidsystem), but they all are quite similar in overall mechanism, although the substances involved and overall effects can vary.

In most cases, aligandbinds to acell 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 ofG protein-coupled receptors,the conformation change exposes a binding site for aG-protein.The G-protein (named for theGDPandGTPmolecules 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 ionsare one type of second messengers and are responsible for many important physiological functions includingmuscle contraction,fertilization,and neurotransmitter release. The ions are normally bound or stored in intracellular components (such as theendoplasmic reticulum(ER)) and can be released during signal transduction. The enzymephospholipase Cproducesdiacylglycerolandinositol 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, activatesprotein kinase C,which assists in the activation of cAMP (another second messenger).

Examples

	cAMPSystem	Phosphoinositolsystem	Arachidonic acidsystem	cGMPSystem	Tyrosine kinasesystem
First Messenger: Neurotransmitters (Receptor)	Epinephrine(α2, β1, β2) Acetylcholine(M2)	Epinephrine(α1) Acetylcholine(M1, M3)	Histamine(Histamine receptor)	-	-
First Messenger: Hormones	ACTH,ANP,CRH,CT,FSH,Glucagon,hCG,LH,MSH,PTH,TSH	AGT,GnRH,GHRH,Oxytocin,TRH	-	ANP,Nitric oxide	INS,IGF,PDGF
Signal Transducer	GPCR/Gs(β1, β2),Gi(α2, M2)	GPCR/Gq	UnknownG-protein	-	RTK
Primaryeffector	Adenylyl cyclase	Phospholipase C	Phospholipase A	guanylate cyclase	RasGEF(Grb2-Sos)
Second messenger	cAMP (cyclic adenosine monophosphate)	IP3;DAG;Ca2+	Arachidonic acid	cGMP	Ras.GTP(Small G Protein)
Secondary effector	protein kinase A	PKC;CaM	5-Lipoxygenase,12-Lipoxygenase,cycloxygenase	protein kinase G	MAP3K(c-Raf)

Second Messengers in the Phosphoinositol Signaling Pathway

IP₃,DAG, and Ca²⁺are second messengers in the phosphoinositol pathway. The pathway begins with the binding of extracellular primary messengers such as epinephrine, acetylcholine, and hormones AGT, GnRH, GHRH, oxytocin, and TRH, to their respective receptors. Epinephrine binds to the α1 GTPase Protein Coupled Receptor (GPCR) and acetylcholine binds to M1 and M2 GPCR.

The phosphoinositol signaling pathway

Binding of a primary messenger to these receptors results in conformational change of the receptor. The α subunit, with the help ofguanine 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 boundphosphatidylinositol 4,5-bisphosphate(PIP₂), resulting in the formation of secondary messengers diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP₃).IP₃binds to calcium pumps on ER, transporting Ca²⁺,another second messenger, into the cytoplasm.Ca²⁺ultimately binds to many proteins, activating a cascade of enzymatic pathways.

External links

• Kimball J."Second messengers".RetrievedFebruary 10,2006.
• Animation: Second Messenger: cAMP