Two receptor parts (alpha and beta) come together, forming a dimer.
The receptor becomes an enzyme, phosphorylating other proteins; this phosphorylation is a key step in signal transduction.
EGF (Epithelial Growth Factor)
Important for skin and nail growth; plays a crucial role in cell proliferation and differentiation.
Ligand binding causes receptors to dimerize, bringing two receptor subunits together.
Auto-phosphorylation occurs at multiple sites, creating a cascade of downstream signaling events.
Phosphorylation sites allow other proteins to bind and relay the signal, amplifying the initial signal.
Two separate receptors come together to activate, forming a functional complex.
Trans-phosphorylation: one kinase phosphorylates the other, activating the receptor complex.
Insulin Receptor
Insulin, alpha and beta subunits are close to each other, forming a complex even before insulin binds.
Subunits are bound by disulfide bonds, stabilizing the receptor structure.
Insulin binding leads to auto-phosphorylation, activating the receptor's kinase activity.
Similar principle to other RTKs: phosphorylation activates downstream processes, triggering a cascade of events that lead to glucose uptake and metabolism.
Signaling Pathways
Cascade effect: IRS-1, SH2 domain, GRB2, SOS, RAS, RAF, MEK, ERK, each activating the next in sequence.
Each step activates the next, amplifying the signal and allowing for regulation at multiple points.
The whole cascade is a target for drug intervention to activate the end process (transcription activation of ERK), offering multiple points for therapeutic intervention.
Glycogen synthesis is regulated by insulin and glucagon, balancing glucose storage and release.
Need to transmit the signal to the nucleus to activate transcription factors, initiating gene expression changes.
Transcriptional factors bind to the nucleus and recruit RNA polymerase to produce transcripts, leading to protein synthesis and cellular changes.
Redundancy in Signaling
Backup systems are in place to maintain control, ensuring robust and reliable signaling.
Multiple effectors ensure signal transmission even if one system fails, providing redundancy in the signaling network.
Having multiple backups prevents diseases, as the system can compensate for failures in individual components.
Kinases and Phosphatases
Kinases add phosphate groups (phosphorylation), turning the signal ON, regulating protein activity and interactions.
Phosphatases remove phosphate groups (dephosphorylation), turning the signal OFF, restoring the proteins to their inactive state.
Dephosphorylation is crucial to prevent constitutive activation, ensuring that the signal is tightly controlled.
Mutations in phosphorylases lead to constitutive activation and chronic disorders, highlighting the importance of proper regulation.
Both kinases and phosphatases are signaling proteins, playing complementary roles in signal transduction.
Reversible reactions control the signal, allowing for dynamic and responsive regulation.
PTKs (Protein Tyrosine Kinases)
Soluble kinases, in contrast to receptor tyrosine kinases that are membrane-bound.
Example: BCR-ABL gene translocation (Philadelphia chromosome), resulting in a constitutively active kinase.
BCR-ABL fusion gene is always switched ON, leading to myelogenous leukemia (CML), driving uncontrolled cell proliferation.
GLEEVAC (imatinib) is an anticancer drug that traps ABL in an inactive conformation by occupying its ATP binding site (competitive inhibitor), effectively shutting down the kinase activity.
Causes remission in 90% of patients, revolutionizing the treatment of CML.
ATP mimics are also being developed as anticancer drugs, targeting other kinases involved in cancer development.
Receptor Tyrosine Kinases summary
Adaptive proteins with specific domains bind to phosphates, mediating protein-protein interactions.
Link RTKs with G proteins and additional kinases, operating as a cascade, integrating different signaling pathways.
GPCRs (G Protein-Coupled Receptors)
Another family of receptors is GPCRs, which are integral membrane proteins that transduce signals via G proteins.
Ligand binding activates a G protein, initiating a signaling cascade inside the cell.
Second messenger systems such as adenylate cyclase or nitric oxide are activated, amplifying the signal and triggering downstream effects.
Phosphoinositide pathway is also involved, providing an alternative signaling route for GPCRs.
GPCRs are super fascinating due to complex and intricate balance of signals, allowing for fine-tuned regulation of cellular processes.
Control senses and bind hormones, mediating a wide range of physiological responses.
The cAMP pathway and other pathways are involved, diversifying the effects of GPCR signaling.
Activating and Deactivating Signals
Signals need to be turned off to prevent constitutive activation, ensuring proper cellular function and preventing disease.
Example: RTK (select one example like insulin receptor), where phosphorylation and dephosphorylation regulate the signal duration and intensity.
GPCRs Details
Around 800 known GPCRs, making them one of the largest and most diverse families of receptors in the human genome.
Function in sight, smell, and taste, mediating sensory perception.
Ligands: catecholamines, adrenaline, noradrenaline, bioactive amines (histamine, serotonin), peptide hormones, lipids, a wide range of signaling molecules.
Target of approximately 30% of pharmaceutical drugs, making them a major focus of drug discovery efforts.
NSAIDs (pain relievers) target some GPCRs, modulating pain and inflammation.
Agonists and Antagonists
Agonists activate signals, mimicking the effects of the natural ligand.
Antagonists block signals, preventing the natural ligand from binding and activating the receptor.
Adrenergic Receptors
Respond to adrenaline, mediating the "fight or flight" response.
Have different impacts on different types of cells, allowing for tissue-specific responses to adrenaline.
Transducer Pathway
Receptor: GPCR that binds to the ligand.
Transducer: taking signal from the receptor to a second message, typically a G protein.
Effector: adenylate cyclase or related enzyme, which generates a second messenger.
The effector causes a signaling cascade, amplifying the signal and triggering downstream effects.
GPCR Signaling
Extracellular molecule binds, activating the receptor, initiating the signaling process.
G proteins are heterodimers anchored to the cytoplasmic side, interacting with the receptor and downstream effectors.
Binding activates GTPase, which activates adenylate cyclase, switching on the enzyme's activity.
Adenylate cyclase generates a secondary message (cAMP), a key signaling molecule in many cellular processes.
Receptor Structure
Seven-pass transmembrane proteins (integral membrane domains), characteristic of GPCRs.
N-terminus is extracellular, C-terminus is intracellular, defining the receptor's orientation in the cell membrane.
Loops form intricate structures for ligand binding, allowing for specific interactions with signaling molecules.
Membrane location side usually between these helices are transmembrane helices that twist when ligand is bound to open up the signal on other side, facilitating signal transduction.
G Proteins: GDP to GTP
Inactive form with GDP, bound to the G protein.
Receptor binding activates it with GTP, triggering a conformational change in the G protein.
GTPase activity deactivates it, hydrolyzing GTP back to GDP and returning the G protein to its inactive state.
Some G proteins activate adenylate cyclase, others inhibit it, allowing for diverse signaling outcomes.
Effector Protein: Adenylate Cyclase
Converts ATP to cAMP, synthesizing the second messenger cAMP.
cAMP targets soluble protein kinases and activates them to phosphorylate other proteins, amplifying the signal and triggering downstream effects.
cAMP is a small, ubiquitous, intracellular secondary messenger, involved in a wide range of cellular processes.
GPCR signaling is rapid compared to RTK signaling, allowing for quick responses to external stimuli.
Adenylate Cyclase Structure
Two transmembrane domains (M1, M2), spanning the cell membrane.
Two cytoplasmic domains (CA1, CA2), interacting with G proteins and ATP.
GTP brings them together to form the active site, enabling cAMP synthesis.
Ending the Signal
Hydrolyze cAMP back to AMP, terminating the signal.
cAMP phosphodiesterases do this, activated by calcium, regulating cAMP levels.
Calcium is stored in the endoplasmic reticulum and released upon cAMP signaling, linking calcium signaling with cAMP signaling.
Phosphorylation by PKA (protein kinase A) is involved, providing feedback regulation of the signaling pathway.
Adenylate Cyclase Signaling System
Stimulatory signal activates GTP, which activates adenylate cyclase to form cAMP, increasing cAMP levels.
Inhibitory signal inhibits adenylate cyclase, decreasing cAMP levels.
Toxins
Cholera toxin blocks GTP and locks it in the active phase, constant signaling, pumping water out of cells, leading to severe dehydration.
Pertussis inhibits GDP for GTP exchange, preventing inhibition of adenylate cyclase, resulting in increased cAMP levels.
Drugs
Caffeine antagonizes adenosine receptors through inhibitory G proteins, leading to excess cAMP production, contributing to its stimulant effects.
Phosphoinositide Pathway
Alternative signaling pathway with GPCRs, utilizing different second messengers.
Ingredients: GPCR, heterotrimeric G protein, phospholipase C, phosphorylated glycerophospholipid (PIP), key components of the pathway.
PIP allows for three secondary messages to be generated: IP3, calcium, and DAG, diversifying the signaling outputs.
DAG activates membrane-bound PKC, triggering a cascade, phosphorylating target proteins and modulating cellular functions.
DAGs
Produced from glycerophospholipids by hydrolysis, initiated by phospholipase C.
Important for lipid synthesis and breakdown, also acting as a signaling molecule.
Phosphorylation
Phosphatidylinositol 4,5-bisphosphate (PIP2) gets phosphorylated to Inositol 1,4,5-triphosphate (IP3), a crucial step in the pathway.
Protein kinase C (PKC) is activated by DAG and calcium, phosphorylating target proteins, mediating various cellular responses.
GPCR Signaling
GTP activates phospholipase C, which cuts up PIP2, generating IP3 and DAG.
Inositol acts as a second messenger, releasing calcium from intracellular stores.
Protein kinase C (PKC) is also an exmaple where DAG is activated. It activates protein kinase C, which then activates other target proteins and so on and so forth, where you have an ultimate response inside the cell, leading to diverse cellular outcomes.
Cellular Processes Controlled by Phosphoinositide
Acetylcholine, vasopressin, thrombin, growth factors activate the cascade, triggering various cellular processes.
Growth factors, fibroblast growth factors leads to DNA synthesis, fertilization, spermatozoa, and so on and so forth, regulating cell growth, proliferation, and differentiation.
Nitric Oxide
Regulates neurotransmission, vasodilation, and immune responses.
Stimulates guanylate cyclase, which converts GTP to cyclic GMP, activating downstream signaling pathways.
Cyclic GMP is terminated by cyclic GMP phosphodiesterase, controlling the duration of the signal.
Viagra is a cAMP phosphodiesterase inhibitor, which sustains blood flow, treating erectile dysfunction.
Originally discovered for heart function, now used for various other conditions.
GPCR Signaling Summary
Integral membrane proteins (seven-pass transmembrane), characteristic of GPCRs.
Hormone binds at specific sites of the GPCR on the outside, initiating the signaling process.
Interaction activates a G protein, initiating a second messenger system, amplifying the signal.
Cyclic AMP activates protein kinase A, leading to phosphorylation of target proteins.
Phosphodiesterases act on CMP and GAMP to linearize them again, terminating the signal.
GPCRs can also signal through the phosphoinositide pathway, providing an alternative route for signal transduction.
Hormone Roles In The Cell
Hormones trigger multiple signaling pathways, regulating various cellular functions.
Signaling pathways are complex: inhibition, activation, effectors, receptors, and signaling proteins, involved in intricate regulatory networks.