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Cell Signaling and Endocrine Regulation Cellular Communication Everything an animal does involves communication among cells Example: moving, digesting food Cell signaling – communication between cells Signaling cell sends a signal (usually a chemical) Target cell receives the signal and responds to it Figure 3.1 Types of Cell Signaling Short distance Long distance Indirect Signaling Direct Signaling Gap junctions Specialized protein complexes create an aqueous pore between adjacent cells Movement of ions between cells Changes in membrane potential Chemical messengers can travel through the gap junction Example: cAMP Circumvents problems of moving a hydrophilic messenger Opening and closing of gap junction can be regulated Signal passed directly from signaling cell to target cell by… Indirect Signaling Short distance Paracrine Chemical messenger diffuses to nearby cell Autocrine Chemical message diffuses back to signaling cell Long distance Endocrine System Chemical messenger (hormone) transported by circulatory system Nervous System Electrical signal travels along a neuron and chemical messenger (neurotransmitter) is released Signaling cell releases chemical messenger Chemical messenger carried in extracellular fluid to target cell Some may be secreted into environment (exocrine) Communication of signal to target cell Chemical messenger binds to a receptor on target cell Activation of signal transduction pathway Response in target cell Table 3.1 Indirect Signaling Exocrine a chemical (pheromone) is released by one individual and travels through external environment to exert its effect on a different individual Figure 3.3 Glands Secretory cells are often organized into glands Ductless Pheromones for animal to animal communication – also other uses Chemical Messengers Six classes of chemical messengers Peptides Steroids Amines Lipids Purines Gases Structure of chemical messenger (especially hydrophilic vs. hydrophobic) affects signaling mechanism Each presents a substantial challenge All known hormones Table 3.2 Indirect Signaling TM – signal is communicated across cell membrane without ligand itself needing to cross the membrane Effects 2 Non-genomic Genomic or Non-genomic Peptide/Protein Hormones 2-200 amino acids long Synthesized on the rough ER Often as larger preprohormones Stored in vesicles Prohormones Secreted by exocytosis Hydrophilic Soluble in aqueous solutions Travel to target cell dissolved in extracellular fluid Bind to transmembrane receptors Signal transduction Rapid effects on target cell Figure 3.4 Synthesis & Secretion of Peptide Hormones Importance of Regulated Exocytosis: Botulism – weakness and paralysis Proteolytic, glycosylation etc. enzymes Figure 3.5 Synthesis & Secretion of AVP Figure 3.6 Peptides bind to Transmembrane Receptors Steroid Hormones Derived from cholesterol Synthesized by smooth ER or mitochondria Three classes of steroid hormones Mineralocorticoids Electrolyte balance Glucocorticoids Stress hormones Reproductive hormones Regulate sex-specific characteristics Synthesis Steroid Hormones Hydrophobic Can diffuse through plasma membrane Cannot be stored in the cell Must be synthesized on demand Transported to target cell by carrier proteins Example: albumin (principal carrier protein in vertebrates) Bind to intracellular or transmembrane receptors Slow effects on target cell (gene transcription) Stress hormone cortisol has rapid non-genomic effects Figure 3.8 Steroid Hormones Law of Mass Action M + C ? M-C Amine Hormones Chemicals that possess amine group (–NH2) Example: acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), serotonin, melatonin, histamine, thyroid hormones Sometimes called biogenic amines Some true hormones, some neurotransmitters, some both Most hydrophilic Thyroid hormones are hydrophobic Behave like steroids! Diverse effects tyrosine => (DOPA) => dopamine => noradrenaline => adrenaline tyrosine hydroxylase DOPA decarboxylase dopamine ß-hydroxylase phenylethanolamine N-methyl transferase Figure 3.10 Other Chemical Messengers Eicosanoids Most act as paracrines Hydrophobic But bind TMR Often involved in inflammation and pain Example: prostaglandins, leukotrienes Aspirin and ibuprofen Other Chemical Messengers Gases Most act as paracrines Example: nitric oxide (NO), carbon monoxide Purines Function as neuromodulators and paracrines Example: adenosine, AMP, ATP, GTP Communication to the Target Cell All classes of chemical messengers bind to… Receptors on target cell Hydrophilic messengers bind to transmembrane receptor Signal communicated inside without ligand Hydrophobic messengers bind to intracellular receptors (some also to transmembrane receptors) Since receptors in cell, easily communicated to other biochemical pathways in cell Ligand Chemical messenger that can bind to a specific receptor Receptor changes shape when ligand binds Ligand-Receptor Interactions Ligand-receptor interactions are specific Only the correctly shaped ligand (natural ligand) can bind to the receptor Ligand mimics Agonists – activate receptors Antagonists – block receptors Many ligand mimics act as drugs or poisons A ligand may bind to more than one type of receptor Receptor isoforms Expressed on different target cells Different responses to the same ligand Eg. Epinephrine A single cell may have receptors for many different ligands No receptor – No response Ligand-Receptor Binding L + R ? L-R Formation of L-R complex causes response More free ligand (L) or receptors (R) will increase the response Law of mass action Receptors can become saturated at high L Response is maximal Changes in Number of Receptors Number of receptors affects number of L-R complexes More receptors ? ? L-R complexes ? ? response Target cells can alter receptor number Down-regulation Target cell decreases the number of receptors Often due to high concentration ligand Up-regulation Target cell increases the number of receptors Figure 3.13b Ligand-Receptor Dynamics Affinity of receptor for ligand affects number of L-R complexes Higher affinity constant (Ka) ? ? response Low Kd = high affinity Figure 3.14 Inactivation of Ligand-Receptor Complex L-R complex must be inactivated to allow responses to changing conditions Signal Transduction Pathways Convert the change in receptor shape to an intracellular response Four components Receiver Ligand-binding region of receptor Transducer Conformational change of the receptor which activates… Amplifier Signal transduction pathway Increase number of molecules affected by signal Responder Molecular functions that change in response to signal Figure 3.15 Transduction Pathway At each step, one molecule can activate many molecules of the next substance in chain Types of Receptors Intracellular Bind to hydrophobic ligands Mostly genomic effects Ligand-gated ion channels Lead to changes in membrane potential Receptor-enzymes Lead to changes in intracellular enzyme activity G-protein-coupled Activation of membrane-bound G-proteins Lead to changes in cell activities Intracellular Receptors Ligand diffuses across cell membrane Binds to receptor in cytoplasm or nucleus L-R complex binds to specific DNA sequences Regulates the transcription of target genes increases or decreases production of specific mRNA 1 2 3 Figure 3.18 Changes in Gene Transcription Cascade of gene regulation acts as amplifier in this signal transduction pathway 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 membrane potential Direct and rapid response Receptor Enzymes Ligand binds to transmembrane receptor Catalytic domain of receptor starts a phosphorylation cascade ? amplification Phosphorylation of specific intracellular proteins G-Protein-Coupled Receptors Ligand binds to transmembrane receptor Receptor interacts with intracellular G-proteins Named for their ability to bind guanosine nucleotides (?) Heterotrimeric (?, ?, ?) Subunits of G-protein dissociate Some subunits activate ion channels Changes in membrane potential Changes in intracellular ion concentrations Some subunits activate amplifier enzymes Formation of second messengers Figure 3.25 G-Protein-Coupled Receptors Table 3.3 Second Messengers Definition:? A short-lived intracellular messenger that acts as an intermediate in a signal transduction pathway GPCRs – enormous diversity - all function through one of the above Figure 3.26 Inositol-Phospholipid Signaling Gq Ca2+ is a third messenger Figure 3.27 Cyclic-AMP Signaling Primarily, ?s and ?i regulate levels of intracellular cAMP Interaction Among Transduction Pathways Cells have receptors for different ligands Different ligands activate different transduction pathways Response of the cell depends upon the complex interaction of signaling pathways E.g. Ca2+-CaM interacts with adenylate cyclase and cAMP PDE Conversely, PKA can phosphorylate Ca2+-channels! Regulation of Cell Signaling Cell signaling is important for regulation of physiological processes Components of biological control systems Sensor Detects the level of a regulated variable Sends signal to an integrating center Integrating center Evaluates input from sensor Sends signal to effector Effector Target tissue that responds to signal from integrating center Effects a change in the regulated variable towards homeostasis Regulation of Cell Signaling Set Point The value of the variable that the body is trying to maintain Feedback loops Positive Output of effector amplifies variable away from the set point Positive feedback loops are not common in physiological systems Negative Output of effector brings variable back to the set point The Regulation of different pathways vary in complexity Figure 3.28 Feedback Regulation Short Distance – paracrine and autocrine Long Distance – nervous and endocrine Naming - # of steps between integrating center and target organ (response) Pituitary Hormones – examples of feedback loops Pituitary gland secretes many hormones Two distinct anatomic sections: Anterior pituitary (adenohypophysis) Posterior pituitary (neurohypophysis) Posterior Pituitary Extension of the hypothalamus Neurons that originate in hypothalamus terminate in posterior pituitary Neurohormones oxytocin and vasopressin synthesized in cell body and travel in vesicles down axons First-order endocrine pathway Hypothalamus receives sensory input Hypothalamus serves as integrating center Anterior Pituitary Hypothalamus synthesizes and secretes neurohormones ? Hypothalamic-pituitary portal system ? Anterior pituitary releases hormones Tropic hormones Cause release of another hormone Third-order endocrine pathway Figure 3.31 Hypothalamus and Anterior Pituitary Tropic Hormones Portal System Regulation of Blood Glucose – Case Study Precisely controlled Blood glucose too low, brain cannot function Blood glucose too high, osmotic balance of blood disturbed Hormones Insulin lowers blood glucose levels Glucagon raises blood glucose levels Regulation of Blood Glucose Insulin and glucagon are secreted by pancreas Direct feedback loops Pancreas also receives neural and hormonal signals Antagonistic pairing Hormones that have opposing effects Figure 3.33 Pathways Regulating Insulin Secretion Direct Second order Figure 3.34 Antagonistic Regulation of Blood Glucose Additivity and Synergism Additivity When hormones cause same response in a target cell Hormones do not use the same signaling pathway Response of target cell to combinations of these hormones is additive Synergism When hormones enhance affect of other hormones Response of target cell to combinations of these hormones more than additive Example: glucagon, epinephrine, and cortisol all raise blood glucose by different mechanisms Figure 3.35 Additivity and Synergism Figure 3.36 Control of Glucose Levels in Arthropods Crustacean hyperglycemic hormone (CHH) Neurohormone from crab eyestalk Secreted in response to low glucose in blood/hemolymph Vertebrate Stress Response – case study 2 Interaction between nervous and endocrine systems Sense organs detect “stress” Interactive physiology Figure 3.38 Adrenal Tissue in Different Vertebrates Catecholamines and glucocorticoids are involved in stress response in all vertebrates, but… location of interrenal (mineralocorticoid and glucocorticoid) and chromaffin (catecholamines) tissue differ across groups Diffuse endocrine tissues ? discrete organs Evolution of Cell Signaling Endocrine systems of animals diverse Suggests multiple evolutionary origins Chemical messengers, receptors, and cell signaling mechanisms of animals share many similarities Suggests a common ancestor who probably used paracrine signaling Unicellular Organisms Can sense and respond to their environment Use mechanisms similar to cell signaling in animals Examples Motile bacteria (prokaryotes): sense and move towards chemoattractants using transmembrane receptor proteins Eukaryotes: Yeast: secrete mating factor pheromones that bind only to receptors on cells of the opposite mating type Slime molds: free-living amoeboid organisms that form multicellular colonies; secrete cAMP to attract other cells that have specific receptors for cAMP Vertebrates and Invertebrates All have nervous systems; except sponges Circulatory systems arose independently in several groups, e.g., arthropods and vertebrates Endocrine systems could only arise in groups with circulatory systems and therefore also arose independently Vert. vs. Invert. Endocrine systems Correlation between the complexity of the endocrine system and the complexity of the body form Invertebrates vs. vertebrates Fewer endocrine glands and most endocrine signaling uses neurohormones More first-order endocrine loops Fewer third-order endocrine loops Vertebrate Hormones Evolutionary changes in way tissues respond to a hormone, rather than a change in hormone molecules Some hormones have same affect in different animals Example: human growth hormone increase growth rate in fish; estrogen from pregnant mares can be used in post-menopausal women Some hormones have a different affect in different animals Example: prolactin stimulates milk production in mammals, inhibits metamorphosis and promotes growth in amphibians, regulates water balance in fish
