Cell Communication: Signals and Receptors

• Lecture 8 focuses on how cells communicate
• Covers cell signaling, major cell surface receptors, signal transduction, secondary messengers, and cellular activities.

Why Cells Communicate

• Cells responds to internal and external signals to function as a whole
• Signals are often chemical, but can also be light, taste, or smell

Local vs. Long Distance Signaling

• Local signaling involves signals acting on nearby target cells
• Growth factors like fibroblast growth factor (FGF1) act in a paracrine manner
• Neurotransmitters act in a synaptic manner, such as acetylcholine (ACh)
• Signals can act on the signaling cell itself in an autocrine manner
• Long distance signaling
• Hormones secreted from endocrine cells travel through the circulatory system to act on target cells
• Insulin secreted from pancreatic beta cells travels through the bloodstream to be detected by various body cells

Three Main Steps of Cell Signaling

• Reception: A signaling molecule binds to a receptor
• Results in a shape or chemical state change in the receptor protein
• Transduction: The altered receptor activates another protein, such as a G-protein or adenylyl cyclase
• The activated protein causes a relay of changes often through "second messengers" like cAMP or IP3
• Multiple other proteins may be activated during this step
• Each activated protein causes a series of changes, which is often via phosphorylation, known as a phosphorylation cascade
• Response: Activated proteins cause one or more functions to occur in the cell

Major Cell Surface Receptors

• The two major types of cell surface receptors are G protein-coupled receptors and ligand-gated ion channel receptors

Receptors Specificity

• The human body sends out many different chemicals and molecules
• Only the target receptors interact with the signal (ligand) to activate signal transduction pathways.
• Specificity comes from the 3D molecular shape of the proteins involved
• The structure determines function

Receptor Location

• Receptors for water-soluble molecules are membrane-bound, such as G Protein Coupled Receptors, Receptor Tyrosine Kinase, and ligand-gated ion channels
• Receptors for lipid-soluble molecules are not membrane-bound
• Located in the cytoplasm or inside the nucleus
• Lipid soluble hormones like testosterone, estrogen, progesterone, and thyroid hormones bind to receptors within the cytoplasm and move to the nucleus as a complex

G-Protein Coupled Receptors (GPCRs)

• Transmembrane proteins
• Pass through the plasma membrane seven times
• Hundreds of different GPCRs exist
• Diverse functions including development and sensory reception (vision, taste, smell)
• GPCRs couple with G proteins
• G proteins are molecular switches that are either on or off depending on whether GDP or GTP is bound
• GTP is guanosine triphosphate, similar to ATP

GPCRs and G-Protein Activation

• At rest, the receptor is unbound and the G protein is bound to GDP, with the enzyme inactive
• A ligand binds the receptor, which then binds the G protein
• GTP displaces GDP, though the enzyme remains inactive
• The activated G Protein dissociates from the receptor, activating the enzyme and eliciting a cellular response
• The G Protein has GTPase activity, promoting its release from the enzyme and reverting back to the resting state
• Conformational changes determine function

Ligand Gated Ion Channels/Receptors

• These channel receptors contain a "gate"
• Binding of a ligand (e.g., neurotransmitter) elicits a change in shape at the specific site on the receptor
• The channel opens/closes as the receptor changes shape
• Ions can pass through the channel (e.g., Na+, K+, Ca2+, and/or Cl-)
• In the nervous system, released neurotransmitters bind as ligands to ion channels on target cells, which propagates action potentials

Signal Transduction Pathways

• Signals are relayed by receptors to target molecules via a cascade of molecular interactions

Phosphorylation Cascade

• Protein kinases are enzymes that transfer a phosphate group from ATP to another protein, activating it
• Series of protein kinases each add a phosphate to the next kinase
• Phosphatases are enzymes that dephosphorylate, removing the phosphate and rendering the protein inactive, but recyclable
• Typically, serine or threonine residues are phosphorylated
• Mutations affecting these residues can be detrimental

Second Messengers: cAMP

• A small molecule included in the cascade
• cAMP, activated by adenylyl cyclase, acts as a second messenger and activates downstream proteins like PKA, which phosphorylates other proteins

Second Messengers: Calcium

• Low [Ca2+] inside the cell (typically ~100nM)
• Very high [Ca2+] outside the cell (more than 1000-fold higher)
• Concentration maintained via calcium pumps
• Pumps pump calcium out of the cell, into the ER, and into mitochondria

Calcium and IP3 in GPCR Signaling

• The activated protein is phospholipase C, which cleaves PIP2 into DAG and IP3
• IP3 diffuses through the cytosol and binds to a gated channel in the ER
• Calcium ions flow out of the ER, down the concentration gradient, and activate other proteins for a cellular response

Why are there so many steps in Signaling?

• Amplifies the response
• Provides multiple control points
• Allows for specificity of response
  • Allows for temporal and spatial control
• Also allows for coordination with other signaling pathways

Cellular Responses

• Cellular responses include activation or regulation of:
• Gene expression
• Alteration of protein function
• Opening or closing of an ion channel
• Alteration of cellular metabolism
• Regulation of cellular organelles or organization
• Rearrangement/movement of the cytoskeleton

Turning Off the Response

• Signals are for a limited time
• Activation usually promotes the start of deactivation, ensuring homeostatic equilibrium, making the cell ready to respond again if required
• cAMP is broken down by phosphodiesterase (PDE) Inhibiting specific PDE's can be a therapeutic approach

Example of Cell Signaling: Fleeing Impala

• Impala senses a cheetah
• Its brain signals the adrenal glands to release adrenaline into the blood
• Signal reception
• Adrenaline binds to a receptor on a muscle cell
• Signal transduction
• Relay molecules transmit the signal, activating an enzyme
• Cellular response
• The enzyme breaks down glycogen, releasing glucose to fuel leg muscles

Adrenalin Stimulation of Glycogen Breakdown

• Adrenalin binds to a GPCR and activates cAMP and two protein kinases in a phosphorylation cascade
• Cascade results in active glycogen phosphorylase which converts glycogen to glucose 1-phosphate
• One adrenalin molecule can result in 108 glucose 1-phosphate molecules!
• Glucose 1-phosphate is then converted to glucose 6-phosphate which can then be used in glycolysis to generate ATP
• Amplifies the response

Receptors Deceived: Coronavirus

• Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the coronavirus (SARS-CoV-2)
• The key surface spike glycoprotein (S protein) allows it to occur.
• ACE2 in the respiratory tract is the lock, and the S-protein on the virus is the key