Cell Signalling 2

Cell Signalling Overview

  • Chapter Title: Cell Signalling Chapter 15

  • Additional Resource: de Araujo, ‘Cross’-Talking about Aspects in Cell Signalling

  • Copyright © Garland Science 2015

G-Protein Coupled Receptors (GPCRs)

  • G-protein coupled receptors (GPCRs) are a significant class of membrane receptors.

  • True Statements about GPCRs:

    • B. Upon binding of a signal molecule, the GPCR undergoes phosphorylation, enabling G-protein binding.

    • C. GPCRs function as guanine nucleotide exchange factors (GEFs) for specific G-proteins.

  • False Statements:

    • A. There are many GPCRs, not just a few.

    • D. GPCRs are integral proteins and commonly consist of a single polypeptide chain, not multiple polypeptides.

Overview of GPCR Signalling

  1. Signalling Pathways:

    • Signal molecules interact with GPCRs, triggering downstream signalling events.

    • Examples of second messengers: cAMP, IP3.

  2. Responses:

    • Activation of genes, enzymes, and ion channels.

  3. Shutting Off Responses:

    • Mechanisms to deactivate signalling pathways.

Major Families of Trimeric G Proteins

  • Four Major Families:

    • I. Gi: Inhibits adenylyl cyclase, leading to decreased cAMP.

    • II. Gq: Activates phospholipase C (PLC), leading to IP3 and DAG production.

    • III. Go: Inhibits Ca2+ channels; activates other kinases.

  • Key Functions:

    • G protein alpha subunits perform signal transduction through direct activation of effector proteins like enzymes and ion channels.

Activation of G Proteins by GPCR

  • Activation Sequence:

    • Signal molecule binds to GPCR, causing it to activate a G protein.

    • The G protein then activates phospholipase C (PLC), leading to the cleavage of PIP2.

    • Cleavage results in the formation of IP3 and DAG—important second messengers.

Role of IP3 and DAG

  • IP3:

    • Opens IP3-gated calcium channels, resulting in a significant influx of Ca2+ into the cytosol, enhancing intracellular signalling.

  • DAG:

    • Works with Ca2+ and phosphatidylserine to activate Protein Kinase C (PKC).

    • Functions as a precursor for eicosanoid synthesis (e.g., prostaglandins).

Calcium Signalling

  • Intracellular calcium fluctuations serve as critical signals for various cellular responses, including:

    • Muscle contraction

    • Secretory processes.

Calmodulin-Dependent Protein Kinases

  • Calmodulin:

    • Binds Ca2+, inducing a conformational change that allows it to interact with and activate other target proteins.

Summary of RTKs

  1. Activated Receptor Tyrosine Kinases (RTKs):

    • Common class of enzyme-coupled receptors, typically involved in cell proliferation and differentiation.

  2. Activation Mechanism:

    • Ligand binding promotes receptor dimerization and transautophosphorylation, generating docking sites for downstream signalling proteins.

JAK-STAT Signalling Pathway

  • Cytokine Receptors: Do not possess tyrosine kinase domains but associate with Janus kinases (JAKs).

  • JAK Activation:

    • Ligand binding induces receptor dimerization, allowing JAKs to phosphorylate each other and the receptor, which creates docking sites for STAT proteins.

TGF-beta Superfamily Signalling

  • Involves receptor serine/threonine kinases and Smad proteins, playing a key role in cellular processes such as cell growth and differentiation.

  • Functionality:

    • Binding of TGF-beta promotes receptor dimerization, activating Smad transcription factors that regulate gene expression.

Receptor Guanylyl Cyclases

  • Function:

    • Convert GTP to cGMP, a secondary messenger involved in various signalling pathways.

Parallel Pathways and Interactions

  • Various signaling pathways in a cell can intersect and influence common targets, thus amplifying the coordinated response to stimuli.

Protein Interactions and Models

  • Cell signalling networks comprise thousands of interactions that can be studied through computational modeling for predictive insights into drug effects and disease dynamics.