Cellular Signalling Systems Notes

Cellular Signalling Systems Overview

Learning Objectives
  • Structure and Function of cellular signaling receptors:
    • G-protein coupled receptors (GPCRs)
    • Catalytic receptors
    • Ion channel-linked receptors
  • G-protein Activation/Deactivation
  • Mechanisms of Toxins: Pertussis and Cholera Toxins
  • Receptor Tyrosine Kinase (RTK) Pathway: Activation and Deactivation
  • Types of Ion Channels
  • Second Messengers: cAMP, DAG, IP3 production and activity
  • Calcium Signaling: Calcium/calmodulin/CaM Kinase pathway
  • Ras-MAP Kinase Signaling: Receptor tyrosine kinase-mediated signaling
G-Protein Coupled Receptors (GPCRs)
  • Characteristics:
    • Largest family of cell-surface receptors.
    • Transmits most signals from the external world (e.g., sight, smell, taste).
    • More than 800 GPCRs identified in humans.
  • Functionality:
    • Ligands can activate multiple GPCRs (e.g., adrenaline acts on at least 9 GPCRs).
    • Uses G proteins to relay signals from outside to intracellular cytoplasm.
  • Structure:
    • Composed of seven transmembrane α-helices (7-TMS) forming a barrel-like structure.
    • Ligand-binding site located at the center of these helices.
G-Proteins
  • Composition: Complex of three subunits: Gα, Gβ, Gγ.
  • States:
    • Inactive: Gα carries GDP, Gα & Gγ are membrane-bound.
    • Active: Gα(GTP) separates from Gβγ.
  • Function: G proteins switch between active and inactive states to relay signals.
Activation and Deactivation of GPCRs

  • Activation:

    • Ligand binding induces a Ligand Induced Conformational Change (LICC) in the GPCR.
    • G-protein acts as a Guanine Exchange Factor (GEF) causing exchange of GDP for GTP on Gα.
    • Active Gα-GTP interacts with effector molecules (e.g., Adenylyl Cyclase).

  • Deactivation:

    • Ligand dissociates from receptor, ending signal.
    • Gα-GTP hydrolyzes to Gα-GDP initiating signal termination.
    • Regulatory proteins (RGS) can enhance GTP hydrolysis.
Types of Secondary Messengers
  1. Cyclic Nucleotides (cAMP)
  2. Inositol Trisphosphate (IP3) and Diacylglycerol (DAG)
  3. Calcium Ions (Ca²⁺)
cAMP as a Key Second Messenger
  • Synthesis: From ATP by adenylate cyclase (AC) triggered by Gαs signaling.
  • Function:
    • Mediates responses to various hormones and stimuli (e.g., breakdown of triglycerides in fat cells).
    • Activates Protein Kinase A (PKA) which phosphorylates target proteins.
Inositol Trisphosphate (IP3) & Diacylglycerol (DAG)
  • Production: From phosphatidylinositol 4,5-bisphosphate (PIP2) by Phospholipase C.
  • Function/Action:
    • IP3: Diffuses through cytoplasm and promotes calcium release from the ER.
    • DAG: Activates Protein Kinase C (PKC) affecting various cellular processes, including insulin signaling.
Calcium Signaling
  • Role: A critical intracellular signal, with low cytosolic levels compared to extracellular and ER/SR stores.
  • Controlled by signaling pathways such as those involving IP3 leading to channel openings and increased cytosolic calcium levels.
  • Calmodulin: Binds calcium and activates downstream kinases like CaM Kinase impacting various cellular responses.
Receptor Tyrosine Kinases (RTKs)
  • Structure: Composed of an extracellular ligand binding domain, a single transmembrane domain, and an intracellular catalytic domain.
  • Function:
    • Ligand binding generally causes dimerization and activation of intrinsic kinase activity leading to auto-phosphorylation of tyrosine residues on the receptor itself and subsequent signaling cascades.
  • Downstream Effects: Activation of Ras-GTP, leading to stimulation of the MAP kinase pathway.
Signaling through the Ras Pathway
  • Ras is a GTPase activated by RTKs.
  • Activation Mechanism:
    • RTKs recruit Ras-GEF activating Ras by exchanging GDP for GTP.
    • Active Ras activates downstream signaling pathways such as the MAP kinase cascade targeting various cellular growth and differentiation processes.