Second Messengers

Signaling pathways are complex systems in which a single extracellular signal can elicit multiple intracellular events, some of which may also be triggered by other signaling pathways or may themselves trigger other intracellular events. “Second messengers” is a term used to refer to a diverse group of small molecules or ions that transmit the extracellular signal initiated by a ligand binding to a cell surface receptor to effector proteins inside the cell. In the resting state, small amounts of second messengers exist in a cell; however, their production can rapidly ramp up once a signal has been received. Once released inside the cell, second messengers bind to their target proteins and alter their properties (activity, localization, availability of reaction sites, stability, etc.), causing a change in the cell’s homeostasis and thus transmitting the message.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview of Second Messengers

Second messengers are intracellular signaling molecules released by the cell in response to first messengers, which are extracellular signaling molecules.

  • First messengers (ligands):
    • Extracellular factors
    • Hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview
    • Neurotransmitters
    • Epinephrine
    • Growth hormone (GH)
    • Serotonin
  • Second messenger categories and their specific functions:
    • Cyclic nucleotides and other soluble molecules: signal within the cytosol
      • Cyclic adenosine monophosphate (cAMP)
      • Cyclic guanosine monophosphate (cGMP)
    • Lipid messengers: originate within cell membranes
      • Diacylglycerol (DAG)
      • Inositol trisphosphate (IP3)
      • Phosphatidylinositol (3,4,5)-trisphosphate (PIP3)
    • Ions: signal within and between cellular compartments
      • Calcium (Ca)
      • Mg
    • Gases and free radicals: can signal throughout the cell and even to neighboring cells
      • NO
      • CO
      • Hydrogen sulfide (H2S)
  • Second messengers can trigger multiple functions, including:
    • Proliferation
    • Differentiation
    • Migration
    • Survival
    • Apoptosis
The second messenger mechanism

General schematic of the second messenger mechanism

Image: “Second Messenger Mechanism” by Lunska. License: Public Domain

Cyclic Nucleotides

Cyclic adenosine monophosphate

  • General properties:
    • Common second messenger seen in fight-or-flight response as well as many other metabolic pathways
    • Derived from adenosine triphosphate (ATP)
  • Synthesis in response to first messenger:
    • First messengers (e.g., epinephrine) bind to extracellular receptors.
    • Cause intracellular activation of G protein subunits of receptor
    • G protein activates adenylyl cyclase.
    • Adenylyl cyclase catalyzes the conversion of ATP to cAMP.
    • Intracellular levels of cAMP increase.
  • Second messenger activity: 
    • cAMP targets protein kinase A (PKA).
    • 2 cAMP molecules bind to PKA → activate it
    • PKA phosphorylates serine or threonine residues on target proteins.
    • Phosphorylation affects the activity of multiple groups of proteins, particularly those regulating the metabolism of sugars, glycogen, and lipids.
    • The intracellular concentration of cAMP, therefore, determines the fraction of PKA in its active form, and thus the rate at which it phosphorylates its substrates.
  • Examples:
    • Epinephrine pathway:
      • Epinephrine binds to the beta-adrenergic receptor of a muscle cell.
      • G protein activation → cAMP levels increase
      • Activation of PKA leads to the activation of glycogen phosphorylase.
      • Increased glycogen breakdown for a fight-or-flight response.
    • The glucagon pathway follows a similar mechanism.

Cyclic guanosine monophosphate

  • Synthesis in response to first messenger:
    • Guanylyl cyclase (GA) activation converts guanosine triphosphate (GTP) to cGMP.
    • GA activation can be triggered by:
      • Membrane-impermeable peptide hormones binding to extracellular membrane receptors
      • NO permeating through the plasma membrane, activating GA found in the cytoplasm
  • Second messenger activity:
    • Increased levels of cGMP → increased activity of cGMP-dependent protein kinase (PKG)
    • PKG phosphorylates proteins that regulate:
      • Ion channel conductance
      • Glycogenolysis
      • Cellular apoptosis
  • Examples: cGMP functions as a signal to: 
    • Relax smooth muscle in blood vessels → vasodilation and increased blood flow.
    • Regulate Na channels in the eye, controlling phototransduction and image transmission to the brain

Lipids

Lipids present in the plasma membrane, such as phosphatidylinositol 4,5-bisphosphate (PIP2), are often modified and utilized as second messengers. Binding of first messengers to receptors can activate lipid-modifying enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. This leads to the hydrolyzation of specific acyl chains or polar head groups on specific lipid groups, which allows them to function as second messengers.

Diacylglycerol and inositol trisphosphate

  • Synthesis in response to first messenger:
    • Binding of ligands to a G protein–coupled receptor (GPCR) (e.g., histamine) or a receptor tyrosine kinase (RTK) (e.g., growth hormone) activates phospholipase C (PLC)
    • PLC cleaves PIP2, creating 2 second messengers: DAG and IP3.
  • Second messenger activity: 
    • IP3 cascade → release of Ca2+ from the endoplasmic/sarcoplasmic reticulum → muscle contraction or hormone release (depending on the type of cell).
    • DAG cascade works with the released Ca2+ from the IP3 pathway to activate protein kinase C → phosphorylation of other proteins.
G protein coupled receptor (gpcr)

G protein coupled receptor (GPCR) activates phospholipase C, which converts PIP2 into IP3 and DAG. IP3 promotes the release of calcium stores in the cell.
GDP: guanosine diphosphate
GTP: guanosine triphosphate

Image by Lecturio.

Phosphatidylinositol (3,4,5)-trisphosphate

  • Synthesis in response to first messenger:
    • Growth factor (first messenger) binds to tyrosine kinase receptors
    • Tyrosine kinase activates phosphoinositide 3-kinase (PI3K)
    • Induces the phosphorylation of PIP2 at the 3′ to produce PIP3, a second messenger
  • Second messenger activity: 
    • PIP3 targets the prosurvival kinase Akt in the cell cytosol.
    • Once bound, Akt moves to the plasma membrane, where it is involved in a complex signal pathway that promotes cell survival and growth.

Ions

  • Overview:
    • Ions and ion gradients have complex signaling roles within cells (e.g., action potential propagation and signal cofactors).
    • Ca and Mg can also function as intracellular second messengers.
    • They can either be released from intracellular stores or imported into the cell from the extracellular space.
  • Ca:
    • In response to signals, such as IP3, intracellular Ca levels can increase dramatically and act as a second messenger by:
      • Individual ions binding to proteins directly, affecting their activity
      • Changes in overall Ca concentration levels triggering calcium sensor proteins that have downstream effects
    • Ca intracellular levels are regulated tightly.
      • Pumps and channels function to store Ca in the ER or remove it from the cell.
      • A buffer protein like parvalbumin can soak up excess calcium.
    • Signal termination: Pumps and channels remove Ca actively from the cell, transporting it to the ER or outside the cell.
  • Mg:
    • Functions as a second messenger similarly to calcium
    • Can further contribute to signaling by antagonizing Ca-signaling activity (Mg reduces Ca levels by inhibiting its transport into the cytosol)

References

  1. Heldin, CH, Lu, B, Evans, R, & Gutkind, JS. (2016). Signals and receptors. Cold Spring Harb Perspect Biol. 8(4):a005900. https://pubmed.ncbi.nlm.nih.gov/27037414/ 
  2. Sassone-Corsi, P. (2012). The cyclic AMP pathway. Cold Spring Harb Perspect Biol. 4(12):a011148. https://pubmed.ncbi.nlm.nih.gov/23209152/ 
  3. Francis, SH, & Corbin, JD. (1999). Cyclic nucleotide-dependent protein kinases: Intracellular receptors for cAMP and cGMP action. Crit Rev Clin Lab Sci. 36(4), 275–328. https://pubmed.ncbi.nlm.nih.gov/10486703/ 
  4. Tsui, MM, & York, JD. (2009). Roles of inositol phosphates and inositol pyrophosphates in development, cell signaling, and nuclear processes. Adv Enzyme Regul. 50(1), 324–37. https://pubmed.ncbi.nlm.nih.gov/20006638/ 
  5. Cantley, LC. (2002). The phosphoinositide 3-kinase pathway. Science. 296(5573), 1655-7. https://pubmed.ncbi.nlm.nih.gov/12040186/ 
  6. Berridge, MJ, Lipp, P, & Bootman, MD. (2000). The versatility and universality of calcium signaling. Nat Rev Mol Cell Biol. 1(1), 11–21. https://pubmed.ncbi.nlm.nih.gov/11413485/ 
  7. Newton, AC, Bootman, MD, & Scott, JD. (2016). Second messengers. Perspectives in Biology. Retrieved November 1, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968160/ 

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