Cell Signaling: Types and Processes

Principles of Cell Signaling

• Signal transduction involves converting one signal into another within a cell
• This process starts when an extracellular signal is received by a receptor, leading to intracellular signaling and altered cell behavior
• Cell communication involves a signaling cell producing an extracellular signal molecule, which is detected by a target cell.
• Target cells use receptors to recognize and respond to specific signal molecules

Types of Signal Molecules

• Cells communicate using various extracellular signal molecules, including proteins, amino acids, nucleotides, steroids, fatty acid derivatives, and dissolved gases
• Hormones: Extracellular signaling molecules transmitted throughout the body via the bloodstream
• Endocrine cells (e.g., in the pancreas): Produce hormones like insulin, regulating glucose uptake
• Paracrine signaling: Signal diffusion occurs locally through extracellular fluid

Intracellular Signaling Processes

• Proteins act as molecular switches, activated or deactivated by adding or removing molecules or energy
• Phosphorylation: Activation or inactivation occurs when a phosphate group is covalently bound or cleaved, protein kinases transfer a phosphate group from ATP to serine, threonine, or tyrosine residues
• GTP binding: Activation occurs when bound to GTP and inactivation when bound to GDP

Cell-Cell Communication Basics

• A signaling molecule is produced, typically via exocytosis
• The signaling molecule is transported to the target cell
• The target cell receptor binds the signaling molecule to receive the signal
• The target cell responds, altering its behavior

Signal Response Variations

• Responses can be fast (seconds to minutes) or slow (minutes to hours)
• Fast Response: Involves pre-existing proteins and alters their activity
• Slow Response: Requires new synthesis, transcription, or translation, leading to changes in gene expression and protein synthesis

Duration of Cell Response

• Cell responses can be transient or permanent
• Transient: Can revert back
• Permanent: Cannot revert back

Nerve Growth Factor (NGF)

• Peptide hormones serve as signaling molecules
• NGF is secreted by organs to attract innervating neurons.
• Sympathetic neurons grow towards the NGF source
• Rita Levi-Montalcini discovered NGF in the 1950s.
• Sympathetic neurons die without NGF signals

Cell Information Processing

• Cells integrate multiple signals to fine-tune responses
• Apoptosis occurs if appropriate signals are absent or inhibited
• Apoptosis prevents poorly functioning cells from surviving (programmed cell death)

Receptors & Signaling molecules

• Cells employ diverse chemical signals, including proteins, peptides, amino acids, nucleotides, and even gases
• Environmental information is also detected via receptors, such as, mechanoreceptors (physical pressure), photoreceptors (light), voltage-gated ion channels (electrical stimulus), and TRP channels (temperature)

Signal Distances

• Endocrine (Public): Long Distance, Hormones are released into the bloodstream for widespread distribution
• Paracrine (Local): Local mediator to talks to a different cell via the extracellular matrix
• Autocrine (Self-Signaling): The cell responds to its own signal through negative feedback, regulating its activity

Specific Cell Targeting

• Neuronal: Specialized paracrine signaling where neurotransmitters are secreted into small synapses
• Neurotransmitters are quickly removed from the synapse, and the cell response depends on the signaling molecule's half-life
• Signaling molecules with quick degradation lead to fast responses, while persistent molecules generate slower responses

Contact-Dependent (Juxtacrine) Signaling

• Requires direct cell contact, either extracellularly via membrane-bound signals or intracellularly via direct cytoplasm connections
• Plasmodesmata in plant cells establish connections

Gap Junctions

• Clusters of intercellular channels allow direct diffusion of ions and small molecules between adjacent cells
• In cardiomyocytes, gap junctions enable rapid action potential spread

Signal Transduction

• Signaling molecules that can't cross cell membranes are large or hydrophilic
• Extracellular receptors are used in the cell membrane for signal-to-cell surface communication

Types of Extracellular Receptors

• Ligand-gated ion channels, G-protein coupled receptors, enzyme-linked receptors

Ligand-Gated Ion Channels

• Ions alter membrane potential and trigger an action potential
• Signal molecules bind, causing conformational change

G-Protein Coupled Receptors (GPCRs)

• Form the largest family of surface receptors and have a similar structure
• GPCRs interact with G-proteins, which have three subunits: α, β, and γ
• GTP-binding proteins (GTP and GDP) act as molecular switches
• α and γ subunits are tethered to the membrane, can have inactivation or activation states

G-Protein Regulation

• Regulated by binding either GTP (active) or GDP (inactive), controlled by regulatory proteins such as GEF and GAP
• Trimeric G proteins relay messages from G-receptors

G-Protein Coupled Receptors

• Upon activation, a G-protein exchanges GDP for GTP, separating into α subunit and βγ complex
• Both components interact with target proteins, with the α subunit binding to other enzymes
• Active time is determined by how long the α subunit holds onto GTP
• G-proteins can regulate ion channels or activate membrane-bound enzymes

Frequent targets for enzyme regulation

• Adenylyl cyclase: Produces cyclic AMP (cAMP)
• Phospholipase C: Produces inositol trisphosphate and diacylglycerol

Acetylcholine effects study notes

• Nerve signals slow heart rate by releasing acetylcholine
• Acetylcholine binds to GPCR, activating the G-protein
• The βγ complex binds to the intracellular face of the K+ channel, opening it

Action Potential Review

• Membrane potential reversal mediates electrical signaling
• Resting membrane potential: ~ -70 mV
• Neurotransmitters can cause depolarization: Membrane becomes less polarized, moving closer to 0 mV

Enzyme-Linked Receptors

• Includes enzyme complexes or enzyme-associated receptors
• Direct intracellular effects differ from GPCRs
• Receptor Tyrosine Kinases (RTKs) has a cytosolic domain phosphorylates tyrosines on intracellular signaling proteins
• Catalytic domain needs binding by an enzyme (direct contact or touch) for activation

Receptor Tyrosine Kinases (RTKs)

• Binding of an extracellular signal often causes two receptors to form a dimer
• Each receptor tail phosphorylates the other, activating kinase domains
• Phosphorylated tyrosines serve as docking sites for intracellular signaling proteins
• Signal complex remains active unless halted by a phosphatase or endocytosis