🦠Cell Biology Unit 11 – Cell Communication and Signal Transduction

Key Concepts and Terminology

• Cell communication enables cells to respond to their environment, coordinate activities, and maintain homeostasis
• Signal transduction the process by which a cell converts an extracellular signal into an intracellular response
• Ligands signaling molecules that bind to specific receptors on the cell surface or within the cell
• Receptors proteins that bind to specific ligands and initiate a cellular response
• Transduction pathways series of biochemical reactions that relay and amplify the signal from the receptor to the target molecule
• Second messengers small, diffusible molecules (cyclic AMP, calcium ions) that relay signals within the cell
• Cellular responses changes in gene expression, metabolism, or behavior in response to a signal
• Feedback mechanisms allow cells to fine-tune their responses and maintain homeostasis (negative feedback, positive feedback)

Types of Cell Signaling

• Autocrine signaling occurs when a cell secretes a signaling molecule that binds to receptors on its own surface
• Paracrine signaling involves the release of local mediators that affect nearby cells (neurotransmitters, growth factors)
• Endocrine signaling utilizes hormones secreted by endocrine glands and transported through the bloodstream to target cells
• Juxtacrine signaling requires direct cell-to-cell contact and is mediated by cell surface molecules (Notch signaling)
• Synaptic signaling a specialized form of paracrine signaling between neurons or between neurons and target cells
• Intracrine signaling involves signaling molecules that act within the cell where they are produced (steroid hormones)
• Pheromone signaling uses chemical signals to communicate between individuals of the same species (mate attraction, alarm signals)

Signal Molecules and Receptors

• Hydrophobic signal molecules (steroid hormones, thyroid hormones) diffuse across the plasma membrane and bind to intracellular receptors
• Hydrophilic signal molecules (peptide hormones, neurotransmitters) bind to cell surface receptors
• G protein-coupled receptors (GPCRs) a large family of cell surface receptors that activate intracellular G proteins upon ligand binding
  • Consist of seven transmembrane domains, an extracellular ligand-binding site, and an intracellular G protein-binding site
• Receptor tyrosine kinases (RTKs) cell surface receptors with intrinsic enzymatic activity that phosphorylate tyrosine residues on target proteins
  • Possess an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain
• Ion channel-linked receptors allow the flow of specific ions across the membrane in response to ligand binding (nicotinic acetylcholine receptor)
• Intracellular receptors bind to hydrophobic signaling molecules and act as transcription factors to regulate gene expression (steroid hormone receptors)

Signal Transduction Pathways

• GPCRs activate G proteins, which dissociate into $\alpha$ and $\beta\gamma$ subunits to regulate various effector proteins (adenylyl cyclase, phospholipase C)
• RTKs dimerize upon ligand binding, leading to autophosphorylation and recruitment of adaptor proteins that initiate downstream signaling cascades
• Mitogen-activated protein kinase (MAPK) cascades a series of sequentially activated protein kinases that amplify signals and regulate cell growth, differentiation, and survival
  • Consist of three main components: MAPK kinase kinase (MAPKKK), MAPK kinase (MAPKK), and MAPK
• Phosphoinositide 3-kinase (PI3K)/Akt pathway regulates cell survival, growth, and metabolism in response to growth factors and insulin
• Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway mediates the effects of cytokines and growth factors on gene expression
• Wnt signaling pathway controls embryonic development, cell fate determination, and cell proliferation through $\beta$-catenin-mediated transcription

Second Messengers and Amplification

• Cyclic AMP (cAMP) produced by adenylyl cyclase in response to GPCR activation, activates protein kinase A (PKA) to phosphorylate target proteins
• Calcium ions ($Ca^{2+}$) released from the endoplasmic reticulum or extracellular space, bind to and activate calmodulin and other calcium-binding proteins
  • Inositol 1,4,5-trisphosphate ($IP_3$) triggers $Ca^{2+}$ release from the ER by binding to $IP_3$ receptors
• Diacylglycerol (DAG) activates protein kinase C (PKC), which phosphorylates various target proteins
• Nitric oxide (NO) a gaseous second messenger that activates guanylyl cyclase to produce cyclic GMP (cGMP)
• Amplification occurs when a single ligand-receptor interaction generates multiple second messenger molecules, leading to a larger cellular response
  • Each GPCR can activate multiple G proteins, and each effector enzyme can produce numerous second messenger molecules

Cellular Responses to Signals

• Changes in gene expression signal transduction pathways can activate or repress transcription factors, leading to altered gene expression patterns
• Modulation of enzyme activity phosphorylation or dephosphorylation of enzymes can increase or decrease their catalytic activity
• Cytoskeletal rearrangements signals can induce changes in the organization of actin filaments and microtubules, affecting cell shape and motility
• Vesicle trafficking and secretion signaling pathways regulate the transport and release of vesicles containing hormones, neurotransmitters, or other molecules
• Cell proliferation and differentiation growth factors and other signals can stimulate cell division and specialization
• Apoptosis (programmed cell death) initiated by death receptors or stress signals, leading to the activation of caspases and controlled cell dismantling

Regulation and Feedback Mechanisms

• Negative feedback inhibition of signal transduction pathways to prevent excessive cellular responses and maintain homeostasis
  • Receptor desensitization prolonged exposure to a ligand can lead to receptor internalization or decreased responsiveness
  • Feedback inhibition of enzymes products of a signaling pathway can inhibit upstream components to limit the response
• Positive feedback amplification of a signaling pathway by its own products, leading to a rapid and robust response
  • Calcium-induced calcium release $Ca^{2+}$ release from the ER can stimulate further $Ca^{2+}$ release, generating a large $Ca^{2+}$ spike
• Cross-talk between signaling pathways allows for integration of multiple signals and fine-tuning of cellular responses
• Spatial and temporal regulation of signaling components ensures specific and localized responses within the cell
  • Scaffolding proteins bring signaling components together to facilitate their interactions and prevent non-specific activation

Real-World Applications and Disorders

• Pharmacological interventions many drugs target components of signal transduction pathways to treat diseases (beta-blockers, antidepressants)
• Cancer therapy targeted therapies inhibit specific signaling pathways that are overactive in cancer cells (RTK inhibitors, MAPK inhibitors)
• Endocrine disorders result from abnormal production, secretion, or response to hormones (diabetes, thyroid disorders)
• Neurodegenerative diseases involve impaired signaling and communication between neurons (Alzheimer's, Parkinson's)
• Sensory transduction the conversion of external stimuli (light, sound, touch) into electrical signals by specialized sensory cells
• Immune system function cytokines and other signaling molecules coordinate the activities of immune cells to mount an effective response
• Stem cell differentiation signaling pathways guide the specialization of stem cells into specific cell types for tissue regeneration and repair