Communication Cellulaire: Signalisation et Récepteurs

• An organism is an organized, hierarchical structure composed of molecules, cells, tissues, and organs
• Each cell is integrated into a communication network to coordinate adaptive changes
• Unicellular organisms also communicate, including bacteria, yeasts, and phages

Chemical Cell Communication

• An emitting cell produces a chemical signal that acts on a receptor of a receiving cell
• This elicits a response through signal transduction pathways

Intracellular Signaling Pathways

• Responses can occur with or without changes in gene expression
• Activation of gene expression is a relatively slow response (minutes/hours), regulated by transcription factors with a significant energy cost
• Faster pathways (seconds/minutes) rely on pre-existing proteins
• When a signal is received, existing proteins are activated, thereby modifying cell behavior

Receptor Types

• Cell surface receptors are anchored in the membrane and bind to hydrophilic ligands that do not cross the lipid bilayer
• Intracellular receptors are located in the cytoplasm or nucleus
• They bind to small hydrophobic molecules that can cross the lipid bilayer

Intercellular Signaling Modes

• Synaptic signaling involves rapid, electrical impulses (10-100 m/s) along a neuron's axon
• At the axon terminal, neurotransmitters are released into the synaptic cleft to act on postsynaptic receptors
• Endocrine signaling is slower but facilitates widespread dissemination
• Endocrine cells secrete hormones that reach target cells via the bloodstream
• Paracrine signaling involves local communication where target cells are near the emitting cell via a local mediator
• Autocrine signaling occurs when cells respond to signals they themselves secrete, leading to coordinated group behavior
• Contact-dependent signaling involves direct interaction via membrane-bound signals
• It's seen in immune responses via antibody/antigen binding
• Gap junctions (Nexus) allow for direct communication and coordinated response to a stimulus
• Plasma membranes of two cells are joined by connexons, facilitating the passage of small molecules such as Ca2+ and AMPc

Extracellular Signals

• Programmed responses, such as survival, division, differentiation, or apoptosis, depend on multiple extracellular signals

Signal Molecules - Hydrophilic

• Interact with membrane receptors
• Includes hormones like hypoglycemic insulin and hyperglycemic glucagon from the pancreas
• Growth hormone (somatotropin) is from the pituitary gland
• Endogenous opioid peptides (endorphins) are secreted by the pituitary and hypothalamus
• They produce a sense of well-being
• Catecholamines include adrenaline and are from tyrosine derivatives
• Acetylcholine is involved in memory and neurotransmission
• Cytokines such as interferons, interleukins, and chemokines are produced during pathogenic attacks
• Polypeptides like epidermal growth factors regulate growth

Signal Molecules - Lipophilic

• Interact with intracellular receptors
• Derived from cholesterol, such as cortisol
• Glucocorticoids like cortisol are involved in lipid/protein degradation and glucose synthesis
• Thyroid hormones like thyroxine/tetraiodothyroxine (T4)
• Excess thyroxine leads to hyperthyroidism
• Gases like nitric oxide (NO)
• They have neurotransmitter, vasodilation and apoptosis regulation functions

Receptors

• They exhibit specificity for substrates
• Sometimes, molecules with similar structures can bind (promiscuity)
• They demonstrate affinity, requiring low ligand concentrations for effective binding
• They have limited saturability due to the number of receptors
• They demonstrate reversibility with weak, non-covalent bindings
• Binding decreases when the ligand concentration decreases
• They exhibit coupling, transmitting signals to the cytosol or nucleus
• Several signaling cascades are possible from a single receptor
• Receptor classifications include nuclear and cytosolic receptors with nuclear translocation and membrane-bound receptors coupled to ion channels, G proteins, or enzymes

Nuclear Receptor Structure

• Domain A/B contains an N-terminal region involved in transcriptional activation; it is poorly conserved
• Domain C contains a DNA-binding domain (DBD) that is well-conserved and mediates receptor binding to DNA
• Domain D is a hinge region that contains a nuclear localization signal
• Domain E contains a ligand-binding domain (LBD) that binds the ligand
• Domain F is a C-terminal region that is variable

Ligand-Receptor Interactions

• Receptors are maintained in an inactive state by Heat Shock Proteins (HSP)
• Upon binding of a ligand, receptors undergo conformational changes
• HSP dissociates, allowing dimerization
• The complex translocates to the nucleus via nuclear pores
• It binds to DNA at response elements
• Co-activators bind and transcription initiates, inducing target gene expression
• The receptor can function as a transcription factor

Hormone Receptors

• They exist as inactive heterodimers bound to a co-repressor
• Upon hormone binding, the receptor undergoes a conformational change
• This causes dissociation of the co-repressor, recruitment of a co-activator and subsequent initiation of transcription

Receptor-DNA Interaction

• Response elements are DNA sequences where proteins bind

Membrane Receptors

• Constant gradients are maintained by active transport
• K+ exits and Na+ enters through passive transport
• Na+/K+ ATPase maintains ion balance

Resting potential

• The inside of the cell is negative relative to the outside
• [Na+] is higher outside than inside
• [K+] is higher inside than outside

Action Potential

• Transient depolarization occurs at the membrane
• It's caused by opening and closing of fast sodium channels
• Cells use communication to initiate muscle contractions and initiate secretions in endocrine cells

Ligand-Gated Ion Channels

• Receptors and ion channels combine as one
• Other receptors are coupled to G proteins & an ion channel

Nicotinic Acetylcholine Receptors

• Neuronal type are heteromeric pentamers: α2β3 or α3β2
• Muscle type are at neuromuscular junctions
• The subunits are α2βγδ
• Cobra venom prevents acetylcholine from binding

G Protein-Coupled Receptors

• An effector can be either an enzyme or an ion channel
• The receptor has a single polypeptide chain with seven transmembrane alpha helices
• It is glycosylated extracellularly and contains intracellular sites for phosphorylation
• The G protein is a heterotrimer with alpha, beta and gamma subunits
• The alpha subunit binds guanine nucleotides (GDP or GTP)

G Protein Activation Cycle

• An unstimulated alpha subunit binds to GDP
• A heterotrimer is formed
• GDP is replaced by GTP, causing dissociation of the alpha subunit
• The alpha subunit interacts with a target protein and is phosphorylated
• The G protein hydrolyzes GTP and recruits the ẞy dimer

Membrane Receptors Coupled To Enzymes

• These come in two types
• Receptors with intrinsic enzyme activity (tyrosine kinase, serine/threonine kinase, guanylate cyclase)
• Those coupled to enzymes

Tyrosine Kinase Receptors

• Activated by growth factors and insulin
• They phosphorylate tyrosine residues
• Ligand binding causes dimerization and autophosphorylation, creating docking sites

Signal Transduction

• SH2 and PTB domains interact with phosphotyrosine residues
• SH3 domains interacts with proline-rich sequences The binding results in variable phosphorylation and recruitment
• Studying the consequences by mutating the coding sequence

Second Messengers

• First messengers (signals) are perceived by receptors and relayed by proteins for intracellular signaling
• They are amplified by small intracellular molecules like cyclic AMP (AMPc) or calcium (Ca2+)

The MAPK Pathway

• The insulin receptor is a heterotetramer with two alpha chains and two beta chains
• The four units have disulfide bonds
• Insulin binds to the Alpha chains and activates intrinsic tyrosine kinase
• Autophosphorylation creates a docking site for IRS1
• The docking recruits IRS1 and GRB2 adaptor proteins
• SOS protein activation leads to activation of the Ras protein
• A phosphorylation cascade causes the successive activation of MAPKKK, MAPKK, and MARK
• MAPK translocation to the nucleus phosphorylates the transcription factors

The AMPc Pathway

• Adenlyate cyclase synthesis transforms ATP into AMPc via the removal of of two inorganic phosphate groups
• AMPc is transformed into 5’-AMP by phosphodiesterase
• Glycogenolysis includes chain with glucose linked by alpha 1-4 and alpha 1-6 glycosidic bonds, important for glucose liberation
• Glycogen phosphorylase is useful in breaking down (Glycogen + P_i ® [Glycogen-1 residue] + glucose-1- Phosphate
• In glycogenolysis, as G protein stimulated adeniylate cyclase, which activates protein Kinase A
• The alpha stimulatory subunits is activated by PKA fixation and phosphorylating phosphorylase kinase

The Phosphoinositide Pathway

• Phosphatidyl-inositol (PI) binds the AG to Inositol by Phosphate groups
• PI-4,5-biphosphate (PI(4,5)P2) is phosphorylated by two kinases
• DAG + IP3, through hydrolysis acts from Phospholipase C beta
• Receptors trigger Ca2+ release via PLC-ẞ activation
• Inositol phosphates modulate contraction and other activities

Signal Pathway Crosstalk

• Different signals yield different responses
• e.g., alpha 1 adrenergic receptors act via PLC-B to increase IP3 and Ca2+, causing contraction
• Beta 2 adrenergic receptors use AC/AMPc for relaxation

Therapeutic Targets of Signal Pathways

• Agonists of Beta 2-adrenergic receptors (e.g., albuterol/ventolin) treat asthma
• Beta 1-adrenergic receptor antagonists (beta blockers) like acebutolol lowers hypertension
• Anti-cancer drugs target proteins with chimeric BCR-ABL and Imatinib

Quorum Sensing

• It regulates gene expression relative to population density
• Autoinducers like N-acyl-homoserine-lactones (AHL) are produced
• Bacteria use quorum sensing to bioluminesce
• In the symbiosis of bioluminescent bacterium "Vibrio fischeri" it’s induced by quorum sensing
• In low densities, little gene expression occurs
• High densities triggers bioluminescence and virulence through the biofilm
• Biofilms have microbial organisms on a surface in which polysaccharides secrete to make bacteria anti-microbial
• It’s an issue of hygiene problems in hospitals and food companies and Legionnaires’ disease and is present as a catheter