Three stages of cell signaling in order

Reception, transduction, response

Epinephrine and Earl Sutherland study

Epinephrine triggers "fight or flight" by stimulating breakdown of the storage polysaccharide glycogen

Bacterial cell signaling origin

Cell signaling originated in bacteria and single-celled eukaryotes via quorum sensing, later adopted by multicellular organisms

Quorum sensing

Lets bacteria sense local population density via concentrated signals, coordinating behaviors like forming a biofilm

Local signaling: direct contact

Can occur through cell junctions connecting adjacent cells, especially important in embryonic development, immune responses, and maintaining adult stem cells

Paracrine signaling

Signaling occurs when secreted molecules travel only short distances to affect nearby cells; growth factors stimulate nearby target cells to grow and divide

Synaptic signaling

A specialized local signaling type in the nervous system where an electrical signal triggers release of neurotransmitters that diffuse across the synapse to the target cell

Endocrine signaling

Long-distance signaling where specialized cells release hormones that travel through the circulatory system to reach target cells elsewhere in the body

Receptor requirement

A target cell's response depends on whether it has a specific receptor that can bind the signaling molecule, and the signal must then be transduced inside the cell before a response occurs

Signaling molecule (Ligand)

Binds specifically to a receptor, fitting like a glove and changing the receptor's shape to activate it

Ligand-induced aggregation

Ligand binding can sometimes cause aggregation of two or more receptor proteins, which mostly sit on the exterior of the plasma membrane

Three major types of plasma membrane receptors

GPCRs, receptor tyrosine kinases, and ion channel receptors

GPCRs (G-protein-coupled receptors)

Cell-surface transmembrane receptors that work with a G protein, which is energy-rich in GTP

GPCR structure

Structurally, GPCRs consist of 7 transmembrane alpha helices; they are the largest group of plasma membrane receptors with more than 800 types identified

GPCR activation mechanism

When a signaling molecule activates the receptor, the cytoplasmic G protein exchanges bound GDP for GTP to become active; the activated G protein then dissociates, diffuses along the membrane, and binds to/activates an enzyme

G protein GTPase activity

The G protein acts as its own GTPase by hydrolyzing GTP back to GDP, shutting the pathway off; receptor binding itself is reversible so these changes are only temporary

RTKs (Receptor Tyrosine Kinases)

Catalyze the transfer of a phosphate group from ATP to a tyrosine on a substrate protein; abnormal RTK function is linked to many types of cancer

4 steps of RTK signaling

Binding of a growth factor (the ligand) -> dimer (two receptor monomers form a complex) -> activation of the tyrosine kinase region -> recognition and activation of relay proteins

RTK vs GPCR pathway activation

Unlike GPCRs, which typically activate only one pathway at a time, a single RTK can trigger 2 or more different transduction pathways at once, helping regulate cell growth and reproduction

Ligand-gated ion channels

Open or close when the receptor changes shape upon ligand binding, controlling flow of ions like Na+ or Ca2+; especially important in the nervous system, and can also occur in organelle membranes like the ER

Intracellular receptors

Receptors located in the cytoplasm or nucleus; because the signal must cross the plasma membrane, these signaling molecules must be small or hydrophobic, such as steroid and thyroid hormones

Transcription factors

When a hormone binds an intracellular receptor, the resulting hormone-receptor complex can act as a transcription factor, turning specific genes on or off

Signal transduction pathway

Typically a multistep process — a cascade of molecular interactions — which helps amplify the signal and provides more opportunities for coordination and regulation

Protein kinases and phosphatases

Protein kinases transfer phosphate groups from ATP to a protein (phosphorylation), acting as relay molecules in a cascade; protein phosphatases rapidly remove those phosphate groups (dephosphorylation), allowing kinases to be reused

Second messengers

Small, nonprotein, water-soluble molecules or ions that spread through the cell by diffusion; the two most common are cyclic AMP and calcium ions

Adenylyl cyclase

The enzyme embedded in the plasma membrane, converts ATP to cAMP in response to an extracellular signal; the cAMP signal doesn't last long because phosphodiesterase converts cAMP back to AMP

Cholera toxin mechanism

A bacterial toxin modifies the G protein so it can no longer hydrolyze GTP to GDP, leaving it permanently active — continuously stimulating adenylyl cyclase and causing intestinal cells to secrete excess salts and water, leading to severe diarrhea

Calcium ions in cell signaling

Calcium ion concentration is normally much higher in the cytosol than outside the cell or in the ER, so even a small numeric change represents a large percentage change; the second messenger inositol trisphosphate (IP3) triggers the ER to release calcium into the cytosol

Cellular response

The final stage of cell signaling, typically regulates protein synthesis (turning genes on/off via transcription factors) or the activity of existing proteins, such as opening/closing an ion channel

Signal amplification

In signal amplification, each step of an enzyme cascade produces far more activated products than the step before — letting a small number of epinephrine molecules ultimately release hundreds of millions of glucose molecules

Specificity in cell signaling

Arises because different cell types express different collections of receptor, relay, and response proteins, so the same signal can produce different effects in different cells

Cross-talk and scaffolding

Pathway branching and cross-talk further help coordinate incoming signals; scaffolding proteins are large relay proteins that hold several other relay proteins together, increasing signaling efficiency

Signal termination

Because receptor binding is reversible, as external signal concentration falls, fewer receptors stay bound and unbound receptors revert to an inactive state — letting the pathway properly terminate and the cell respond to a fresh signal

Apoptosis overview

Programmed cell death, triggered in cells that are infected, damaged, or at the end of their functional lives; components are chopped up, packaged into vesicles, and digested by phagocytic cells — preventing enzymes from leaking out and damaging neighboring cells

Caspase pathways and Cytochrome c

Humans have about 15 different caspase pathways for apoptosis; one major pathway involves Cytochrome c, normally used in electron transport, which acts as a "death factor" when leaked from mitochondria

Triggers of apoptosis

Apoptotic signals can originate from outside the cell (a death-signaling ligand binding a surface receptor) or from inside, due to irreparable DNA damage or excessive protein unfolding in the ER

Apoptosis in development and disease

Apoptosis is a normal part of development — for example, shaping hands and feet/paws — but is also implicated in diseases like Parkinson's (interference may contribute) and cancers (excessive apoptosis or failure can contribute)

Epinephrine mechanism in Sutherland's experiment

Epinephrine cannot cross the cell membrane because it's water-soluble, so it just binds to a GPCR on the membrane, which starts the signaling pathway leading to glycogen breakdown

GPCRs vs RTKs signal pathways

GPCRs typically activate one pathway at a time, while RTKs activate multiple pathways; because RTKs regulate cell growth and reproduction, abnormal RTK signaling can cause uncontrolled cell growth and contribute to cancer

Cholera toxin vs. normal termination mechanism

Cholera toxin prevents the G protein from turning itself off by stopping it from converting GTP to GDP; the G protein stays active, continuously stimulating adenylyl cyclase and producing too much cAMP, which causes severe diarrhea

Signaling specificity in liver vs heart cells

Liver and heart cells can both respond to epinephrine but have different relay and response proteins, causing glycogen breakdown in liver cells but increasing heart rate in heart cells

Why apoptosis is essential and what happens when it malfunctions

Apoptosis removes unnecessary or damaged cells and is important for normal development (such as separating fingers and toes); if it malfunctions, too many surviving cells can contribute to cancer, while excessive apoptosis can contribute to neurodegenerative diseases like Parkinson's and Alzheimer's