Cell Signaling and Signal Transduction

Overview of Cell Signaling

• Cells are in constant communication with each other and their environments.
• Cells must be able to detect and respond to appropriate signals.
• Cell signalling is essential for organismal development, tissue organization, coordination of activities, and control of growth and division in multicellular organisms.
• Single-cell organisms require cell signalling to adapt to environmental changes.

Signal Transduction

• Signal transduction converts an extracellular signal into a cellular response.
• Cells adapt to changes in their function or structure by signal transduction.

Types of Signals

• Common signal types include chemical, physical, endogenous (internal), and exogenous (external) signals.
• Endogenous signals are generated internally and include endocrine, paracrine, autocrine, and plasma membrane-attached protein signals.
• Exogenous signals originate outside the organism and include photons of light, odors, medications, and invading microorganisms.

Endogenous Chemical Signals

Endocrine Signaling

• Uses hormones that are released into the bloodstream.
• Hormones access distant target cells, examples include insulin and epinephrine.

Paracrine Signaling

• Signal is released by a nearby cell onto a target cell.
• It creates a gradient of signalling molecules like neurotransmitters and growth factors.

Autocrine Signaling

• An autocrine signal acts on the cell that released it.
• Includes cytokines and certain growth factors.

Plasma Membrane-Attached Protein Signaling

• Signaling molecules embedded in the plasma membrane of one cell activate receptors on another cell through direct contact.
• Molecules may also be cleaved from the membrane to become soluble signals.
• Adhesion molecules on immune cells are an example.

Cellular Receptors

• Receptors facilitate specific signal selectivity.
• They enable graded responses based on the signal amount.
• The same signal may produce different responses across different cell types.
• Receptors amplify signals.
• Most signals need plasma membrane receptors to initiate intracellular responses because they cannot cross the plasma membrane.

Receptor Function

• Ligands or agonists bind to receptors, where a ligand is any molecule that binds, and an agonist is a ligand that activates the receptor.
• Receptor activation involves a conformational change signaling the presence of a ligand.

Key Properties of Cellular Receptors

• Cells respond to signals only with the appropriate receptor.
• Receptors are proteins sensitive to and physically interacting with signals.
• A ligand is a molecule that can tightly bind to and activate a receptor; it is also known as a receptor agonist.

Signal Binding and Cellular Changes

• Ligand binding causes the receptor to undergo a conformational change, activating an intracellular transduction pathway.
• This conformational change leads to the enzymatic activity of the receptor, the opening of pores for ion flow, the activation of a bound kinase, or the activation of a G-protein.

Plasma Membrane Receptors

• Detect signals that cannot cross the plasma membrane.
• These receptors have three regions:
  • An extracellular domain that binds signal molecules, possessing a specific binding site.
  • A transmembrane domain embedded in the plasma membrane which transmits signals.
  • An intracellular domain typically associated with enzymes or proteins that help transduce the signal which then activates signaling.

Plasma Membrane Receptor Classes

• G-protein coupled receptors.
• Ligand-gated ion channels.
• Enzyme-linked receptors.

G-Protein Coupled Receptors

• The receptor interacts with a heterotrimeric G-protein.
• Ligand binding causes the G-protein to dissociate from the receptor.
• Activated G-proteins interact with intracellular targets to regulate cell function.

Ligand-Gated Ion Channels

• Ligand binding to the receptor causes the opening of a pore.
• Ions flow freely through this pore.

Enzyme-Linked Receptors

• The receptor either has intrinsic enzyme activity or associates with an enzyme.
• Ligand binding to the receptor causes enzyme activation.

Intracellular Receptors

• Intracellular Receptors can detect signaling molecules that have crossed the plasma membrane, such as steroids and thyroid hormones.
• They typically regulate gene expression.

Ligand Binding

• Ligands bind to the receptor's binding site through numerous weak, non-covalent interactions.
• Affinity is the strength of interaction between a ligand and its receptor, and specificity is the receptor’s ability to discriminate between different ligands.
• Molecules binding to an allosteric site can modify the degree of receptor activation by a ligand.

Factors Affecting the Magnitude of Cellular Response

• Amount of signalling molecule: response increases with concentration.
• Affinity of receptor: Higher affinity leads to response at lower dosage.
• Receptor expression: increasing numbers of receptors leads to increased maximal response.
• Presence of Competitive Antagonists: Compete with agonists, increasing the required agonist concentration for desired effect.
• Presence of Non-Competitive Antagonists: Binds to allosteric site or irreversibly to the binding site, inhibiting the receptor.

Intracellular Signal Transduction Pathways

• Receptor activation doesn't directly change cell function; proteins or small molecules transduce the signal.

Common Pathways

• Second messenger systems.
• Protein phosphorylation/dephosphorylation.
• GTP-binding proteins.

Second Messengers

• Small molecules that are produced following receptor activation.
• Examples: cAMP, Ca2+, IP3, DAG, cGMP.
• Second messengers amplify signal, transmit signal from plasma membrane to cytosol, and activate targets to propagate the signal.

Cellular Responses

• Examples: Proliferation, apoptosis, contraction, secretion, movement, differentiation, and altered metabolism.
• Main mechanisms: modification of existing proteins and changes in gene expression.
• Modification of existing proteins can occur via phosphorylation/dephosphorylation, binding to second messengers, binding to nucleotides, or binding to upstream signalling proteins that then alter the target protein's conformation.

Phosphorylation/Dephosphorylation

• Protein phosphorylation refers to adding a phosphate group to a protein, performed by protein kinases.
• Protein dephosphorylation refers to removing a phosphate group, performed by protein phosphatases.
• Phosphorylation modifies the function of the target protein, modifies enzyme activity, generates binding site for additional protein, and causes protein dimerization.
• Phosphorylation typically occurs on tyrosine, serine, and threonine amino acids, and provides molecular memory of pathway activation.

Protein Kinases

• Protein Kinases may be cytosolic, intrinsic to a receptor, or attached to a receptor.
• They add phosphates to specific amino acids.
• Tyrosine kinases vs. serine/threonine kinases are examples
• They are directed to a phosphorylation site by the surrounding amino acid sequence.
• Protein Kinases phosphorylate more than one target protein.
• Proteins can have multiple phosphorylation sites which allows for complex regulation of function.
• Protein Kinases are directly activated after ligand binding to a receptor.
• Receptor tyrosine kinases can also be under the control of second messengers. An example being protein kinase A.

Protein Phosphatases

• Protein Phosphatases exhibit specificity like protein kinases.
• They remove phosphate groups from specific amino acids like tyrosine or serine/threonine.
• Protein Phosphatases dephosphorylate specific substrates.
• Kinases and phosphatases are regulated through phosphorylation.