Signal Transduction

Signal Transduction

Signal transduction is the process by which cells communicate with each other and respond to their environment. It involves the conversion of signals from one form to another, such as converting a chemical signal into an electrical signal or vice versa. This process is critical for a wide range of cellular processes, including growth, development, differentiation, metabolism, and the response to environmental stresses.

In signal transduction, a signal molecule, also called a ligand, binds to a receptor on the surface of the cell or within the cell. This binding event triggers a cascade of signaling events inside the cell, which ultimately leads to a response. The response can be a change in gene expression, alteration of enzyme activity, or modification of protein function, among others.

Structure

• Tyrosine kinase structure
  • dimeric transmembrane protein
  • intrinsic kinase activity
  • phosphorylated receptor can bind protein called insulin receptor substrate (IRS)
    • is a scaffold protein
• Pathway
  • hormone binds to receptor
  • receptor is dimerized
  • auto cross-phosphorylation of intracellular domain of the dimerized receptor
  • IRS binds phosphorylated domian
  • IRS is phosphorylated on SH2-domains
  • several enzymes bind phosphorylated SH2-domians
    • phosphatases
      • pathway signaled for by insulin
    • kinases
      • phosphoinositol-3 (PI-3) kinase
    • G proteins
      • ras
        • oncogene present in many cancer
        • constitutive activation leads to constant growth signal
• Examples
  • insulin, PDGF, EGF receptors
  • sensitization via PPAR-gamma 
• G protein signaling

• G-protein structure
  • trimeric enzyme
    • α, β, γ
      • α-subunit has intrinsic GTPase activity
        • acts as timer for shutting off the active form
• Pathway
  • hormone binds to receptor:G-protein complex on cell membrane
  • GDP bound to inactive α-subunit is exchanged for GTP
  • α-subunit now active
    • can be inhibitory (G_i) or stimulatory (G_s, G_q)
  • is released from β, γ subunits
  • can act as 2 different effector mechanisms
    • cAMP pathway
      • G_s activates adenyl cyclase
        • normally, ATP → cAMP to increase [cAMP]
        • cAMP can activate protein kinase A
        • Cholera and E. coli toxins
          • ADP-ribosylates subunit of G_s, which activates G_s 
          • ↑↑↑ [cAMP]
      • G_i inhibits adenyl cyclase
        • normally, stops ATP → cAMP to decreases [cAMP]
        • Pertussis toxin
          • ADP-ribosylates subunit of G_i, which inhibits G_i
          • ↑↑↑ [cAMP]
    • PIP₂ pathway
      • G_q activates phospholipase C
        • PIP₂ → IP₃ + DAG
          • DAG can activate protein kinase C
          • IP₃ can release Ca²⁺ from the ER
            • Ca²⁺ then activates a number of enzymes including protein kinase C
  • GTP eventually hydrolyzed to GDP and α-subunit becomes inactive
• Examples
  • cAMP = glucagon, epinephrine (β, α₂)
  • PIP₂ = vasopressin, epinephrine (α₁)

full list given in G-protein-linked 2nd messengers topic 

cGMP signalling

• Pathway
• hormone binds to receptor on cell membrane
• there is also a soluble receptor in the cytoplasm
• receptor has intrinsic guanylate cyclase activity
• GTP → cGMP
• cGMP activate protein kinase G
• protein kinase G mediates smooth muscle relaxation/vasodilation
• no G protein required
• Examples
• ANF → cell membrane receptor
• NO → diffuses across cell membrane and binds soluble receptor
• mechanism for pharmacologic nitrates (nitroprusside, nitroglycerine)

Stages of Signal Transduction

Signal transduction involves multiple stages, each of which is essential for the proper transmission of signals between cells. The following are the general stages of signal transduction:

1. Reception: The first stage of signal transduction is the reception of the signal molecule by the receptor protein on the surface of the cell. The receptor protein can either be a transmembrane protein that spans the cell membrane or an intracellular protein.
2. Transduction: After the receptor protein binds with the signal molecule, it initiates a cascade of signaling events within the cell. This stage is called transduction, and it involves the transfer of the signal from the receptor to other proteins within the cell.
3. Amplification: Once the signal is transduced, it is often amplified, meaning that the signal is increased in strength or intensity. This amplification ensures that the cell responds appropriately to the signal.
4. Response: The final stage of signal transduction is the cellular response, which can be any number of cellular activities, such as gene expression, enzyme activity, or protein modification.

Overall, signal transduction is a highly regulated process that involves multiple stages, each of which is essential for the proper transmission of signals between cells.

Signal Transduction Pathways

Signal transduction pathways are the specific signaling events that occur within cells in response to a specific stimulus or signal. There are several different types of signal transduction pathways, including:

1. G protein-coupled receptors (GPCRs) pathway: GPCRs are a family of transmembrane receptors that interact with G proteins. When a ligand binds to a GPCR, it causes a conformational change in the receptor, which activates a G protein. The activated G protein then triggers a cascade of signaling events within the cell.
2. Receptor tyrosine kinase (RTK) pathway: RTKs are transmembrane receptors that are activated by ligand binding. When a ligand binds to an RTK, it causes the receptor to dimerize and activate its intracellular tyrosine kinase domain. The activated tyrosine kinase domain then triggers a cascade of signaling events within the cell.
3. Intracellular signaling pathways: Intracellular signaling pathways involve signaling events that occur within the cell, rather than on the cell surface. These pathways can be activated by a variety of signals, including intracellular molecules and extracellular signals that are transported across the cell membrane.
4. Ion channel receptors pathway: Ion channel receptors are transmembrane proteins that form a channel that allows ions to pass through the cell membrane. When a ligand binds to an ion channel receptor, it causes a conformational change in the receptor that opens the ion channel and allows ions to flow through.

Overall, signal transduction pathways are complex and highly regulated processes that play a critical role in cellular communication and response. The specific pathway that is activated depends on the type of signal and the receptor that is activated.

Complications

Signal transduction is a complex process that is essential for normal cellular function. However, abnormalities in signal transduction pathways can lead to various complications and diseases. Some examples of signal transduction complications include:

1. Cancer: Many types of cancer are caused by mutations in genes that regulate signal transduction pathways. These mutations can lead to uncontrolled cell growth and division, which is a hallmark of cancer.
2. Diabetes: Diabetes is a metabolic disorder that is caused by abnormalities in insulin signaling pathways. Insulin is a hormone that regulates glucose metabolism in the body, and disruptions in insulin signaling can lead to high blood sugar levels and other metabolic complications.
3. Neurological disorders: Abnormalities in signal transduction pathways can also lead to neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and schizophrenia.
4. Cardiovascular diseases: Signal transduction pathways also play a critical role in cardiovascular health. Abnormalities in these pathways can lead to conditions such as hypertension, atherosclerosis, and heart failure.

Overall, abnormalities in signal transduction pathways can lead to a wide range of complications and diseases. Understanding these pathways and developing therapies to target them is critical for the prevention and treatment of many diseases.

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