Physiology Unit 1 CELL SIGNALING: CHEMICAL MESSENGERS AND SIGNAL TRANSDUCTION PATHWAYS

Physiology Unit 1 CELL SIGNALING: CHEMICAL MESSENGERS AND SIGNAL TRANSDUCTION PATHWAYS

In Physiology Today

Cell Communication Homeostatic mechanisms maintain a normal balance of the body s internal environment Control systems (Negative Feedback) require cells to be able to communicate with each other Cellular communication is mostly by chemical messengers (Ligands) Neurotransmitters Paracrine Agents Rapid Released by cell Short distance Binds to neighboring cells Hormones Autocrine agents Slower Released by cell Longer distance Binds to self cell Gases

Lipid Soluble Messengers Lipid soluble messengers can easily diffuse through the plasma membrane Messengers bind to intracellular receptors Usually bind to DNA Activated receptor acts as a transcription factor Lipid soluble messengers Cortisol Steroid hormones Thyroid hormones

Water Soluble Messengers Water soluble messengers can not diffuse through the plasma membrane Must bind to receptor in the plasma membrane Water soluble messengers Peptide hormones Neurotransmitters Paracrine/autocrine compounds

Receptors How cells detect chemical messengers Receptor has a binding site for the chemical messenger Chemical messenger tells the cell what to do

Characteristics of Receptors Specificity Single messenger Multiple messengers Affinity Saturation Competition Antagonists Agonists

Competition for Receptors Messengers with a similar structure compete for binding sites on receptors Antagonists Blocks the endogenous messenger and prevents the response Agonists Binds to receptor and triggers the cells response Mimics endogenous messenger

Regulation of Receptors Receptors are subject to regulation Number of receptors Affinity of receptors Down-regulation Persistent, high [chemical messenger] Desensitizing Up-regulation Prolonged, low [chemical messenger] Hypersensitivity

Ligand Gated Ion Channels Receptor activation opens an ion channel Increases membrane permeability of that ion Ion diffuses across the plasma membrane Changes membrane potential Examples: Many neurotransmitters

Receptor Tyrosine Kinases Intrinsic enzyme activity Regulates Cell proliferation Cell differentiation Apoptosis Receptor activation includes activation of the enzyme Examples Growth factors Insulin

Receptors That Activate JAK Kinase Receptor activation activates the associated JAK kinase JAK kinases phosphorylate transcription factors Examples Prolactin GH Many cytokines

G-Protein-Coupled Receptors Very common G-protein complex bound to a receptor Receptor activation results in dissociation of the α sub-unit α-sub-unit activates an ion channel or an enzyme in the plasma membrane Examples: Many neurotransmitters Many hormones

Water Soluble Messengers Pathway Components Pathway Components 1. Receptor Activation 2. Receptor activation generates a second chemical messenger in the cytoplasm 3. Signal transduction: a series of chemical reactions that result in the cells response Protein kinase Any enzyme that phosphorylates other enzymes or proteins by transferring a phosphate group from ATP Activates the enzyme or protein Changes the conformation of the phosphorylated protein

Signal Transduction Pathways Receptor activation is the initial step Messenger-receptor binding causes a conformation change in the receptor Examples of a cells response: Permeability Transport properties Voltage change in the membrane Cell metabolism Cell secretory activity Cells contractile activity Protein synthesis

Signal Transduction Signal transduction pathways convert chemical signals to a biologically meaningful response Sequence of events from binding of a chemical messenger to the cells response

Source Cyclic AMP (camp) 2nd messenger 1st messenger activates a G-protein coupled receptor G-protein activates adenylyl cyclase Adenylyl cyclase converts ATP to camp Action: camp activates camp-dependent protein kinase A Protein kinase A activates a large number of different proteins Initiates an amplification cascade camp may also de-activate enzymes

Cyclic AMP (camp) 2nd messenger Phosphodiesterase deactivates camp to AMP

Signal Amplification by camp

Source Diacylgylerol (DAG) 2 nd messenger 1 st messenger activates a G-protein coupled receptor G-protein activates Phospholipase C Phospholipase C splits a plasma membrane phospholipid to diacylglycerol (DAG) Action Activates protein kinase C Protein kinase C activates other intracellular proteins

Inositol Triphosphate (IP 3 ) 2 nd messenger Source 1 st messenger activates a G-protein coupled receptor G-protein activates Phospholipase C Phospholipase C splits a phospholipid to inositol triphosphate (IP 3 ) Action - IP 3 Binds to ligand gated Ca 2+ channels on the smooth ER - Ligand-gated Ca 2+ channels open and increase cytoplasmic [Ca 2+ ]

DAG and IP 3 2 nd messengers Protein Kinase C is activated by DAG and Ca 2+

Calcium (Ca 2+ ) 2 nd messenger Source - In the plasma membrane: - Ligand gated Ca 2+ channels - Voltage gated Ca 2+ channels - G-protein activates Ca 2+ channels - Ca 2+ released from the smooth ER (mediated by IP 3 or Ca 2+ entering the cytoplasm) - Active transport of Ca 2+ is inhibited by a 2 nd messenger Action - Ca 2+ activates calmodulin - Activates calmodulin-dependent protein kinases - Ca 2+ binds to and alters protein activity directly

Calcium (Ca 2+ ) 2 nd messenger Remember active transport systems in the plasma membrane and organelles maintain low cytoplasmic [Ca 2+ ]

Source Arachidonic Acid 2 nd messenger 1 st messenger binds to a g-coupled receptor G-protein activates Phospholipase 2 Phospholipase 2 splits off arachidonic acid from a membrane phospholipid Action Produces eicosanoids Cyclooxygenase (COX) pathway or lipoxygenase (LOX) pathway Eicosanoids may act as 2 nd messengers or as local paracrine/autocrine agents

Arachidonic Acid 2 nd messenger NSAIDS block the COX pathway reduce pain, fever, inflammation Adrenal steroids inhibit phospholipase A 2 blocks the production of all eicosanoids Eicosanoids are produced from arachidonic acid Prostaglandins Thromboxanes Leukotrines

Eicosanoids Prostaglandins, Thromboxanes, Leukotrines Signaling molecules in CNS Hormones Paracrine/paracrine agents Sometimes called super hormones Derived from Omega-3 and Omega-6 fatty acids Involved in inflammation and immunity Very complex control systems vcortisol inhibits eicosanoid production

Stopping Signal Transduction Pathways Chronic overstimulation in cells can be detrimental Presence of 2 nd messengers are transient Physiological controls to stop receptor activation 1.Enzymes in the vicinity metabolize the 1 st messenger 2.Phosphorylating the receptor May decrease it s affinity for the messenger May prevent further binding of G-proteins binding to the receptor 3. Endocytosis of messenger-receptor complex