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

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.

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)