Comparative Animal Physiology (BIOL 3060) Lecture 3 PDF

Comparative Animal Physiology (Biol 3060) Professor: Dr. Michael Cardinal-Aucoin Fall 2024 Cell-Cell Communication Indirect and direct signalling Types of chemical messenger Mechanism of action Receptor-ligand interactions Biol 3060 - Dr. M. Card...

Comparative Animal Physiology (Biol 3060) Professor: Dr. Michael Cardinal-Aucoin Fall 2024 Cell-Cell Communication Indirect and direct signalling Types of chemical messenger Mechanism of action Receptor-ligand interactions Biol 3060 - Dr. M. Cardinal-Aucoin 2 Cellular Communication Animals are multicellular. Everything an animal does involves communication and coordination among cells. – Example: moving, digesting food. Cell signaling – communication between cells – Signaling cell sends a Signal cell Target cell signal (usually a chemical) – Target cell receives the signal and responds to it Biol 3060 - Dr. M. Cardinal-Aucoin 3  Cells can detect the stimuli in their extracellular environment for which they have the appropriate receptor. stimulus receptor Cell growth, morphogenesis, differentiation. Detected by Movement (e.g. cell a specific chemotaxis, phototaxis). receptor response Change in metabolism. Stimuli: Aggregation and mating Light cues. Chemical Programmed cell death Mechanical cell (apoptosis) pressure Etc. Altered gene expression. Signal transduction mechanism Regulation of metabolic converts external environmental pathways signal into an internal cellular Etc. signal. Biol 3060 - Dr. M. Cardinal-Aucoin 4  E.g. Paramecium Positive Bacteria (i.e. chemotaxis food) Negative chemotaxis movement Amoeba (i.e. predator) Positive phototaxis Light Detection of stimulus leads to changes in ciliary beating – altered movement. Biol 3060 - Dr. M. Cardinal-Aucoin 5  Coordination and regulation in multicellular organisms requires extracellular signaling molecules for communication between cells. signaling molecule receptor for the signaling molecule delivery to a specific release a target cell response in the target cell synthesis signaling cell target cell In multicellular organisms, signaling molecules are synthesized and released by signaling cells and produce a specific response only in target cells that have receptors for the signaling molecules. Biol 3060 - Dr. M. Cardinal-Aucoin 6  General Signaling Pathway (cell surface receptors) Cells respond to signals via signal transduction pathways. May involve: second messengers Molecular switches Effectors Signal amplification Response Amplification means can respond strongly to low levels of signal Biol 3060 - Dr. M. Cardinal-Aucoin 7 The Speed and length of a Response Depends on a variety of factors Nature of response (ion channel, movement, gene expression) Turnover time of signaling molecules Feedback loops Biol 3060 - Dr. M. Cardinal-Aucoin 8 Feedback Loops affect duration and intensity of a response Positive feedback: output (B) further stimulates A- a transient extracellular signal can induce a longterm change in the cell. Negative feedback: output (B) inhibits A – can keep response short and/or weaker Biol 3060 - Dr. M. Cardinal-Aucoin 9 Feedback Loops affect duration and intensity of a response Signal kinase activates (phosphorylates) E kinase. E kinase then further stimulates its own phosphorylation. I (dephosphorylates E) acts slowly. Positive feedback can increase strength of response and can cause it to continue long after stimulus. Biol 3060 - Dr. M. Cardinal-Aucoin 10 Feedback Loops affect duration and intensity of a response Signal kinase activates (phosphorylates) E kinase. E kinase then phosphorylates I to increase activity of I, which in turn decreases activity of E kinase. Activity may be lower and/or oscillate Biol 3060 - Dr. M. Cardinal-Aucoin 11  Cells Can Adjust Their Sensitivity to a Signal Cell Adaptation or Desensitization Prolonged exposure to the stimulus decreases the cell’s response. Mechanisms: Biol 3060 - Dr. M. Cardinal-Aucoin 12 Signal transduction: the process of converting an extracellular signal (signaling molecule A) into an intracellular signal (signaling molecule B) in a target cell. The intracellular signal initiates a series of intracellular reactions that regulate metabolism, movement, proliferation, survival, and differentiation of the target cell. extracellular signaling receptor for the extracellular molecule A signaling molecule A intracellular signaling molecule B Metabolism Movement Proliferation target Survival cell Differentiation Signal transduction Biol 3060 - Dr. M. Cardinal-Aucoin 13  Six steps in cell signaling: (1) synthesis of the signaling molecule by the signaling cell (2) release of the signaling molecule by the signaling cell (3) transport of the signaling molecule to the target cell (4) detection of the signal by a specific receptor protein (5) a change in cellular metabolism, function, or development triggered by the receptor-signaling molecule complex (6) removal of the signaling molecule, which terminates the cellular response Biol 3060 - Dr. M. Cardinal-Aucoin 14 Types of Cell Signaling Two types of cell signaling 1) Direct signaling 2) Indirect signaling Direct signaling – Signaling cell and target cell connected by gap junctions. – Cytoplasm passes between the cells. – Signal passed directly from one cell to another. ▪ E.g. wave of depolarization Biol 3060 - Dr. M. Cardinal-Aucoin 15  Based on: the distance over which the signal molecule acts the speed with which the signal molecule is delivered to its target cell the selectivity with which the signal molecule is delivered to its target cell, Cell signaling can be classified into 5 types: 1. Direct (contact-dependent) cell-cell signaling 2. Paracrine signaling 3. Autocrine signaling 4. Endocrine signaling 5. Neuronal signaling Biol 3060 - Dr. M. Cardinal-Aucoin 16  1. Direct (contact-dependent) cell-cell signaling signaling cell receptor membrane-bound signaling molecule target cell In direct (contact-dependent) cell-cell signaling, a signal molecule anchored in the plasma membrane of the signaling cell binds to a receptor molecule embedded in the plasma membrane of the target cell. Direct (contact-dependent) cell-cell signaling requires cells to be in direct membrane-to-membrane contact with each other. Direct (contact-dependent) cell-cell signaling does not require the release of a signaling molecule. Biol 3060 - Dr. M. Cardinal-Aucoin 17  2. Paracrine signaling signaling cell neighboring target cell neighboring target cell receptor signaling molecule neighboring target cell In paracrine signaling, the signaling molecules released by a signaling cell into the extracellular medium act locally to affect target cells in close proximity to the signaling cell. Biol 3060 - Dr. M. Cardinal-Aucoin 18  3. Autocrine signaling receptor signaling molecule In autocrine signaling, cells respond to signaling molecules that they themselves release. This type of signaling is particularly common in cancer cells, which overproduce and release growth factors that stimulate inappropriate, unregulated growth and division of themselves; this process leads to cancer development. Biol 3060 - Dr. M. Cardinal-Aucoin 19  4. Endocrine signaling endocrine cell receptor blood vessel hormone Hormone, from Greek meaning ‘to set in motion.’ distant target cells In endocrine signaling, signaling molecules, called hormones, act on target cells distant from their site of synthesis by endocrine cells. Hormones produced in endocrine cells are secreted into the bloodstream and can be distributed widely throughout the body. Biol 3060 - Dr. M. Cardinal-Aucoin 20  5. Neuronal signaling receptor electrical impulse axo n target Neurotransmitter cell body cell (signaling molecule) neuron (a nerve cell) In neuronal signaling, signals are transmitted from the cell body of a neuron (a nerve cell) along the axon to remote target cells. When activated by signals from the environment or from other nerve cells, the neuronal cell body sends electrical impulses along the axon at speeds of up to 100 meters per second. Biol 3060 - Dr. M. Cardinal-Aucoin 21  5. Neuronal signaling receptor electrical impulse axo n target Neurotransmitter cell body cell (signaling molecule) neuron (a nerve cell) On reaching the axon terminal, the intracellular electrical signals stimulate the terminal to secrete extracellular signaling molecules called neurotransmitters. Neurotransmitters produce a specific response in target cells that have receptors for the neurotransmitters. Often causes opening or closing of ion channels leading to changes in electrical properties of target cell. Biol 3060 - Dr. M. Cardinal-Aucoin 22 Biol 3060 - Dr. M. Cardinal-Aucoin 23  Each Cell Is Programmed to Respond to Specific Combinations of Extracellular Signals Biological response to extracellular signal molecule depends on: a) cell type b) types and combinations of signal molecules Biol 3060 - Dr. M. Cardinal-Aucoin 24 Types of Cell Signaling Indirect Signaling cell releases chemical messenger. Chemical messenger carried in extracellular fluid. – Some may be secreted into environment. Chemical messenger binds to a receptor on target cell. Activation of signal transduction pathway. Response in target cell. Biol 3060 - Dr. M. Cardinal-Aucoin 25  Indirect Signaling 4 types of indirect signaling: 1. Paracrine ▪ Chemical messenger diffuses to nearby cell 2. Autocrine Short distance ▪ Chemical message diffuses back to signaling cell 3. Endocrine ▪ Chemical messenger (hormone) transported by circulatory system 4. Nervous Long distance ▪ Electrical signal travels along a neuron and chemical messenger (neurotransmitter) is released Biol 3060 - Dr. M. Cardinal-Aucoin 26 Short Distance Communication Autocrine – Common in immune system – E.g. interleukin-1 (a cytokine) released by monocytes Paracrine – Common in immune system, reproductive system; also neurotransmitters. – E.g. prostaglandins local regulators of vasodilation and inflammation. Biol 3060 - Dr. M. Cardinal-Aucoin 27 Long Distance Communication Multicellular organisms require mechanisms to regulate and coordinate cellular activity throughout the organism. Two forms of long distance communication in animals: 1. Nerves – rapid and transient 2. Hormones – slow and long lasting Intimately linked into neuroendocrine system involved in homeostatic control. – Some nerves stimulate hormone – Some nerves (neurosecretory cells) produce hormones – Some hormones act on nerves Biol 3060 - Dr. M. Cardinal-Aucoin 28 The Body’s Long-Distance Regulators Animal hormones are chemical signals secreted into the circulatory system, and communicate regulatory messages within the body. Hormones reach all parts of the organism, but only target cells have receptors for that hormone and therefore only they respond. The endocrine system secretes hormones that function in the maintenance of homeostasis and regulate almost every aspect of physiology, development, and behaviour. Biol 3060 - Dr. M. Cardinal-Aucoin 29 Signaling by Pheromones Members of an animal species sometimes communicate with pheromones. These are chemicals that are released into the environment. Pheromones serve many functions, including: – marking trails leading to food – defining territories – warning of predators – attracting potential mates Biol 3060 - Dr. M. Cardinal-Aucoin 30 Summary: Types of Cell Signaling Biol 3060 - Dr. M. Cardinal-Aucoin 31 Indirect Signaling Common mechanism: 1. Release of chemical 1. Release messenger from signaling cell (gland). 2. Transport 2. Transport of messenger through extracellular environment to target cell. 3. Communication 3. Communication of signal to target cell Biol 3060 - Dr. M. Cardinal-Aucoin 32 Indirect Signaling Biol 3060 - Dr. M. Cardinal-Aucoin 33 Tripathy et al., (2015) Indian Journal of Endocrinology and Metabolism, 19(1)143-147. Biol 3060 - Dr. M. Cardinal-Aucoin 34 Aliberti et al. (2001) Physiol. Res. 50: 231-235. Biol 3060 - Dr. M. Cardinal-Aucoin 35 Types of Chemical Messengers – 6 classes of chemical messengers: 1. Peptides (e.g. oxytocin) 2. Steroids (e.g. estrogen) 3. Amines (e.g. norepinephrine) 4. Eicosanoids (e.g. prostaglandins) 5. Purines (e.g. adenosine) 6. Gases (e.g. nitric oxide, NO) – Chemistry of chemical messenger (especially hydrophilic vs. hydrophobic) affects signaling mechanism. Biol 3060 - Dr. M. Cardinal-Aucoin 36 Peptides 2-200 amino acids long Synthesized on the rough ER – Often as larger preprohormones Stored in vesicles – Prohormones Secreted by exocytosis Biol 3060 - Dr. M. Cardinal-Aucoin 37 Peptides – Hydrophilic (e.g. insulin) ▪ Soluble in aqueous solutions Protein ▪ Travel to target cell dissolved in extracellular fluid – Bind to transmembrane receptors ▪ Signal transduction ▪ Rapid effects on target cell Effect on target cell Signal transduction Biol 3060 - Dr. M. Cardinal-Aucoin 38 Steroids Derived from cholesterol Synthesized by smooth ER or mitochondria (tubular christae) Three classes of steroid hormones 1. Mineralocorticoids (aldosterone) ▪ Electrolyte balance 2. Glucocorticoids (cortisol) ▪ Stress hormones 3. Reproductive hormones ▪ Regulate sex-specific characteristics – (testosterone) Biol 3060 - Dr. M. Cardinal-Aucoin 39  Testosterone Steroids Hydrophobic – Can diffuse through plasma membrane. – Cannot be stored in the cell (= synthesized on demand). – Bind to intracellular or transmembrane receptors. Slow effects on target cell (gene transcription). – Stress hormone cortisol has rapid non-genomic effects. Biol 3060 - Dr. M. Cardinal-Aucoin 40 Steroids Circulate bound to carrier proteins to protect from degradation and to keep steroid in solution. Sex hormone-binding globulin (SHBG) is a glycoprotein that binds to the two sex hormones: testosterone and estrogen. Some bound to albumin. Biol 3060 - Dr. M. Cardinal-Aucoin 41 Steroids Only a very small fraction (1- Testosterone 2%) is unbound, or "free," and thus biologically active. Bioavailability of sex hormones is influenced by the level of SHBG. The relative binding affinity of various sex steroids for SHBG is: dihydrotestosterone (DHT) > testosterone > androstenediol > estradiol > estrone Biol 3060 - Dr. M. Cardinal-Aucoin 42 Biogenic amines Biogenic amines possess amine group (–NH2) – Examples: acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), serotonin, melatonin, histamine, thyroid hormones. Some are true hormones, some neurotransmitters, some are both. Most are hydrophilic however thyroid hormones are hydrophobic. They have very diverse effects. Biol 3060 - Dr. M. Cardinal-Aucoin 43 Biogenic amines Biol 3060 - Dr. M. Cardinal-Aucoin 44  Eicosanoids Most act as paracrines. Synthesized from fatty acid components from cell membranes. Hydrophobic. Often involved in inflammation and pain. – Example: prostaglandins, leukotrienes Biol 3060 - Dr. M. Cardinal-Aucoin 45 Other Chemical Messengers – Gases ▪ Most act as paracrines ▪ Examples: nitric oxide (NO), carbon monoxide – Purines ▪ Function as neuromodulators and paracrines. – Examples: adenosine, AMP, ATP, GTP Biol 3060 - Dr. M. Cardinal-Aucoin 46 Application The enzyme cGMP- specific phosphodiesterase 5 (PDE5) breaks down cGMP, ending muscle relaxation. Sildenafil inhibits PDE5 thus enhancing blood vessel dilation. Biol 3060 - Dr. M. Cardinal-Aucoin X 47 Cellular Response Pathways Water-soluble hormones: – Are secreted by exocytosis – travel freely in the bloodstream – bind to cell-surface receptors Biol 3060 - Dr. M. Cardinal-Aucoin 48 Chemical Classes of Intercellular Signaling Factors Synthesized There are three major Synthesized by Synthesized from cholesterol classes of chemical translation in from aa’s in in SER and ribosomes cytosol messengers in animals: mitochondria – Polypeptides (proteins and peptides) – Steroid hormones – Biogenic amines derived from amino acids The solubility properties of each are important for how they function. Biol 3060 - Dr. M. Cardinal-Aucoin 49 Types of Receptors 1. Intracellular – Binds to hydrophobic ligands and alters transcription 2. Ligand-gated ion channels – Lead to changes in membrane potential (instantaneous) 3. Receptor-enzymes – Lead to changes in intracellular enzyme activity 4. G-protein-coupled – Activation of membrane-bound G-proteins – Lead to changes in cell activities Biol 3060 - Dr. M. Cardinal-Aucoin 50 1. Intracellular Receptors Hydrophobic ligand diffuses across cell membrane Binds to receptor in cytoplasm or nucleus. L-R complex binds to specific DNA sequences. Regulates gene transcription. – i.e. transcription factor Biol 3060 - Dr. M. Cardinal-Aucoin 51 1. Intracellular Receptors Large numbers of genes can get turned on by a single transcription factor. Many genes are often associated with a specific phenotype. Altering transcription is not limited to hydrophobic ligands. Biol 3060 - Dr. M. Cardinal-Aucoin 52 2. Ligand-Gated Ion Channels Ligand binds to transmembrane receptor. Receptor changes shape opening a channel. Ions diffuse across membrane. Ions move “down” their electrochemical gradient. Movement of ions changes the membrane potential. e.g. acetylcholine Biol 3060 - Dr. M. Cardinal-Aucoin 53 3. Receptor Enzymes – Ligand (e.g. insulin) binds to transmembrane receptor. – Catalytic domain of receptor starts a phosphorylation cascade. – Phosphorylation of specific intracellular proteins brings about a change in the cell. Biol 3060 - Dr. M. Cardinal-Aucoin 54  55 Biol 3060 - Dr. M. Cardinal-Aucoin Copyright © 2018 Pearson Canada Inc. 45 - 55 4. G-Protein-Coupled Receptors Ligand binds to transmembrane receptor. Receptor interacts with intracellular GTP binding- proteins. Subunits of G-protein dissociate and activate other membrane-associated proteins and produce second messengers (e.g. cAMP). Biol 3060 - Dr. M. Cardinal-Aucoin 56 Pathway for Water-Soluble Hormones Epinephrine binds to receptors on the plasma membrane of liver cells. This triggers the release of messenger molecules that activate enzymes. One of the responses in the cell is the activation of an enzyme that breaks down glycogen, which results in the release of glucose into the bloodstream. Biol 3060 - Dr. M. Cardinal-Aucoin 57 Cellular Response Pathways Lipid-soluble hormones: – diffuse across cell membranes – travel in the bloodstream bound to transport proteins – diffuse through the membrane of target cells – Bind to receptors in the cytoplasm or nucleus Biol 3060 - Dr. M. Cardinal-Aucoin 58 Pathway for Lipid-Soluble Hormones The response to a lipid-soluble hormone is usually a change in gene expression. When a steroid hormone binds to its cytosolic receptor, the hormone-receptor complex moves into the nucleus. Once in the nucleus, the complex acts as a transcription factor, regulating transcription of specific target genes. Biol 3060 - Dr. M. Cardinal-Aucoin 59 Multiple Effects of Hormones The same hormone may have different effects on target cells that have: – Different receptors – Different signal transduction pathways For example, the hormone epinephrine can increase blood flow to major skeletal muscles, but decrease blood flow to the digestive tract. Biol 3060 - Dr. M. Cardinal-Aucoin 60 Onset and Duration of Hormone Action The time required for hormone effects to take place varies greatly, from almost immediate responses to hours or even days. The time required for duration of hormone action ranges from about 20 minutes to several hours, depending on the hormone. These are affected by: – The type of receptor and signal transduction pathway – Rate of hormone synthesis Hormone – Rate of hormone inactivation concentration – The number of receptors Biol 3060 - Dr. M. Cardinal-Aucoin 61 Ligand-Receptor Interactions Only target cells, or cells that have specific receptors, will respond to the hormone’s presence. – The strength of this response will depend on: ▪ Blood levels of the hormone ▪ The relative numbers of receptors for that hormone on or in the target cells ▪ The affinity (or strength of interactions) of the hormone for the receptor. Biol 3060 - Dr. M. Cardinal-Aucoin 62 Ligand-Receptor Interactions Ligand mimics – Agonists – activate receptors – Antagonists – block receptors – Many ligand mimics act as drugs or poisons. Synthetic ligands can bind even more tightly or selectively than the normal one. E.g. Morphine is an agonist to opioid receptors. Biol 3060 - Dr. M. Cardinal-Aucoin 63 Ligand-Receptor Binding L + R  L-R – Formation of L-R complex leads to the physiological response. – More free ligand (L) or receptors (R) will increase the response ▪ Law of mass action Receptors can become saturated at high L concentration. – Response is maximal Biol 3060 - Dr. M. Cardinal-Aucoin 64 Changes in Number of Receptors The number of receptors affects number of L-R complexes – More receptors →  L-R complexes →  response Target cells can alter receptor number by regulating gene expression: More receptors = more binding Down-regulation – Target cell decreases the number of receptors. Up-regulation – Target cell increases the number of receptors. Biol 3060 - Dr. M. Cardinal-Aucoin 65 Ligand-Receptor Dynamics – Affinity of receptor for ligand affects number of L-R complexes. ▪ Ligands w/ high affinity will remain bound Higher affinity receptors = more binding longer and dissociate less. ▪ Higher affinity constant (Ka) →  response. Kd = dissociation constant Ka = affinity constant = 1/ Kd Biol 3060 - Dr. M. Cardinal-Aucoin 66  Inactivation of Ligand-Receptor Complex – L-R complex must be inactivated to allow responses to subside: changing conditions. – 6 mechanisms of inactivation. Biol 3060 - Dr. M. Cardinal-Aucoin 67 Inactivation of Ligand-Receptor Complex Inhibition of Neurotransmitter Signaling Inactivation inactivation acetylcholine usually broken down (inactivated) by acetylcholinesterase. Activity inhibited by organophosphates E.g. insecticides (malathion, parathion), nerve gas (sarin) antihelmintics (trichlorfon) Biol 3060 - Dr. M. Cardinal-Aucoin 68 Summary of Chemical Messengers Biol 3060 - Dr. M. Cardinal-Aucoin 69