Lecture 17-20 PSC2002

Course Information

  • Course: PSC2002 – Membrane Transport and Cell Signalling in Health & Disease

  • Topics Covered:

    • Cell Signalling Strand covering Lectures 17-20

    • Focus on

      • The phosphoinositide signalling pathway

      • Calcium ion (Ca2+) signalling

  • Instructor: Tim Cheek, Biosciences Institute

    • Contact: tim.cheek@ncl.ac.uk; Ext 87010

  • Printing: Access slides via canvas.ncl.ac.uk under PSC2002 modules

Ca2+ Signalling Overview

  • Functions and Mechanisms (Lectures 17-19)

  • Remodelling in Disease (Lecture 20)

Basic Features of Cell Communication

  • Components:

    • Secreting Cell: Sends chemical signal

    • Target Cell: Receives signal

      • Actions include:

        • Metabolism

        • Response e.g. Contraction, growth, excitability

Signal Reception and Processing Pathways

  1. Steroid Hormones

  2. Ligand-Gated Ion Channels/Receptor-Operated Channels

  3. Cyclic AMP Pathway

  4. Phosphoinositide Pathway

  5. Tyrosine Kinase Pathway

  • Calcium Signalling: Important in many of these pathways

Functions of Intracellular Ca2+ Signalling

  • Responses Include:

    • Ion permeability

    • Metabolism

    • Contraction

    • Secretion of hormones, growth factors, neurotransmitters

    • Development processes, signaling in various organisms (plants, fish, insects, etc.)

Regulation of Ca2+ Concentration

  • Typical intracellular Ca2+ concentration maintained around 100 nM

  • Pumps and Transport Mechanisms:

    • PMCA (Plasma Membrane Ca2+ ATPase)

    • SERCA (Sarcoplasmic Reticulum Ca2+ ATPase)

    • Na+/Ca2+ Exchanger

    • Mitochondria involvement and buffering proteins (e.g. parvalbumin)

ON and OFF Mechanisms of Ca2+ Signalling

  • Calcium Concentration Ranges:

    • OFF mechanisms operate over different ranges (0.01 – 1000 nM)

    • Variability based on resting and stimulated states in various cellular compartments (plasma membrane, mitochondria, endoplasmic reticulum)

Types of Ca2+ Signals

  • Elementary Events: Localized Ca2+ releases

  • Global Ca2+ Waves: Coordinated responses over large areas

  • Global Responses: Involves multiple cell types, contributing to various physiological processes

The Phosphoinositide (PI) Pathway

  • Mechanism:

    1. Chemical signal causes a conformational change in the receptor

    2. Activation of G protein (Gq)

    3. Phospholipase C (PLC) is stimulated

    4. Products:

      • Diacylglycerol (DAG)

      • Inositol 1,4,5-trisphosphate (IP3)

    5. DAG stimulates Protein Kinase C (PKC); IP3 mediates Ca2+ release from the endoplasmic reticulum

    6. Calcium-induced calcium release (CICR) enhances the signal further

Physiological Functions Induced by Ca2+ Signals

  • Processes include:

    • Smooth muscle contraction

    • Mitosis

    • Gene transcription

    • Neurotransmitter release

    • Skeletal muscle contraction

Cell Signalling in Disease Context

  • Remodelling of Signalling Pathways:

    • Example: Phenotypic remodelling (e.g., in heart and liver) during exercise or regeneration

    • Genotypic remodelling leading to conditions like Alzheimer’s Disease → abnormal calcium signalling patterns.

    • Differences in signalling due to pathological conditions may lead to altered cellular functions.

  • Potential Therapies:

    • Targeting Ca2+ signalling pathways for disease treatment (e.g. neurodegeneration)

Conclusion

  • Understanding Ca2+ signalling is crucial for comprehending cell communication functions in health and disease. The interplay of signalling pathways can highlight both normal physiological processes and pathological conditions, paving the way for targeted therapies.

Course Information

Course: PSC2002 – Membrane Transport and Cell Signalling in Health & Disease

Topics Covered:

  • Cell Signalling Strand comprising Lectures 17-20, highlighting critical pathways in cellular communication.

Focus Areas:

  1. The Phosphoinositide Signalling Pathway

  2. Calcium Ion (Ca2+) Signalling

Instructor Details:

  • Instructor: Tim Cheek, affiliated with the Biosciences Institute

  • Contact Information: Email: tim.cheek@ncl.ac.uk; Phone Ext: 87010

  • Access to Materials: Lecture slides and resources available via canvas.ncl.ac.uk under the PSC2002 modules section.

Ca2+ Signalling Overview

Core Concepts:

  • Overview of Ca2+ signalling provided in Lectures 17-19

  • Examination of pathological Remodelling in Disease discussed in Lecture 20

Basic Features of Cell Communication:

Components:

  1. Secreting Cell: Responsible for sending chemical signals (such as hormones) to target cells.

  2. Target Cell: Receives the chemical signal and carries out appropriate responses.

Actions Include:

  • Metabolism: Response of target cells through energy production processes.

  • Response Mechanisms: Varying actions such as muscle contraction, growth processes, and overall excitability of cells.

Signal Reception and Processing Pathways:

Types of Pathways:

  1. Steroid Hormones: Involve intracellular receptors in target cells for slower responses.

  2. Ligand-Gated Ion Channels: Open in response to specific ligand binding, allowing ions to flow across membranes.

  3. Receptor-Operated Channels: Similar to ligand-gated channels but regulated by the receptor interaction with other signaling molecules.

  4. Cyclic AMP Pathway: Actively involves cyclic AMP as a key second messenger.

  5. Phosphoinositide Pathway: Critical for signal transduction involving phospholipids.

  6. Tyrosine Kinase Pathway: Plays a significant role in cell growth and differentiation.

  7. Calcium Signalling: Essential in many of the aforementioned pathways, facilitating various cellular processes.

Functions of Intracellular Ca2+ Signalling:

Key Responses Include:

  • Ion Permeability: Modulates the passage of ions across cell membranes, influencing excitability and signaling.

  • Metabolism: Influences metabolic pathways to balance energy usage and production.

  • Contraction: Initiates muscular contractions in both smooth and cardiac muscle types.

  • Secretion: Promotes the release of hormones, growth factors, neurotransmitters influencing communication between cells.

  • Development Processes: Involved in orchestrating developmental signals across various organisms including plants, fish, insects, and mammals.

Regulation of Ca2+ Concentration:

  • Typical intracellular Ca2+ concentration maintained at a low level around 100 nM.

Pumps and Transport Mechanisms:

  • PMCA (Plasma Membrane Ca2+ ATPase): Responsible for extruding Ca2+ from the cell, maintaining low intracellular levels.

  • SERCA (Sarcoplasmic Reticulum Ca2+ ATPase): Pumps Ca2+ into the sarcoplasmic reticulum, crucial for muscle function.

  • Na+/Ca2+ Exchanger: Utilizes the sodium gradient to transport Ca2+ out of the cell while bringing Na+ in.

  • Mitochondrial Involvement & Buffering Proteins: Proteins such as parvalbumin help to sequester and stabilize calcium levels within the cell.

ON and OFF Mechanisms of Ca2+ Signalling:

  • The Calcium Concentration Ranges are important, with OFF mechanisms operational over different thresholds (0.01 – 1000 nM), reflecting the variance in cellular states depending on resting and stimulated conditions across cellular compartments such as plasma membrane, mitochondria, and endoplasmic reticulum.

Types of Ca2+ Signals:

  1. Elementary Events: Involves localized Ca2+ releases within specific regions of the cell.

  2. Global Ca2+ Waves: Reflect coordinated Ca2+ signaling that spreads over large areas, affecting a larger cellular context.

  3. Global Responses: Multi-cellular implicated responses contributing to broader physiological processes, such as tissue responses.

The Phosphoinositide (PI) Pathway:

Mechanism:

  1. Chemical Signal Activation: A chemical signal facilitates a conformational change in the receptor.

  2. G Protein Activation: Activation of G protein (specifically Gq) sets off the signaling cascade.

  3. Phospholipase C (PLC) Stimulation: This enzyme is activated following the preceding steps.

Products of the Cascade:

  • Diacylglycerol (DAG): Plays a key role in enzyme activation and signaling pathways.

  • Inositol 1,4,5-trisphosphate (IP3): Essential for mobilizing Ca2+ from the endoplasmic reticulum to the cytosol.

Further Amplification Mechanism:

  • Calcium-Induced Calcium Release (CICR): This enhances the Ca2+ signaling response, contributing to larger physiological functions.

Physiological Functions Induced by Ca2+ Signals include:

  • Smooth Muscle Contraction: Regulates blood flow and pressure.

  • Mitosis: Ca2+ signaling facilitates cell division and replication.

  • Gene Transcription: Influences expression of specific genes in response to extracellular stimuli.

  • Neurotransmitter Release: Key in synaptic transmission and neuronal communication.

  • Skeletal Muscle Contraction: Critical for voluntary muscle movements.

Cell Signalling in Disease Context:

Remodelling of Signalling Pathways:

  • Example: Phenotypic remodelling observed during conditions like heart failure or liver regeneration from exercise.

  • Genotypic Remodelling: Alterations lead to pathological conditions such as Alzheimer’s Disease characterized by abnormal calcium signaling patterns that may lead to cellular dysfunction.

Implications of Differences in Signalling:

  • Pathological conditions may result in significant alterations in cellular functions, presenting challenges in maintaining homeostasis.

Potential Therapies:

  • Targeting Ca2+ signalling pathways offers avenues for potential treatments in conditions such as neurodegeneration.

Conclusion:

Understanding and exploring Ca2+ signalling is paramount for comprehending the complexities of cell communication functions in both healthy and diseased states. The interplay between various signalling pathways provides insights into normal physiological processes and highlights trajectories for targeted therapeutic interventions.