Cell Signaling and Endocrine Regulation.docx

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University of Toronto Scarborough
Biological Sciences
Jason Brown

Chapter 3: Cell Signaling and Endocrine Regulation: Pages 90-121  Communication between cells occur when a signalling cell sends a signal to a target cell, usually in the form of a chemistry messenger  Adjacent cells communicate directly through aqueous pores in the membrane called jap junctions  Most cell signalling is indirect, and requires a cell to release a chemical messenger o Chemical messenger travels through extracellular fluids till it hits a target cell o At the target cell the messenger binds to receptor, and changes the shape of the receptor and activates the signal transduction pathway (conformation of a receptor protein on that target cells is causes a change in the activity of that cell)  Chemical messenger travel from a signalling cell to a target cell by diffuse in a process called paracrine communication o A chemical messenger involved in signaling between nearby cell (through diffusion) o These messengers can affect signaling by autocrine communication (a type of signaling in which a single cell signals another cell of the same type) o However rate of diffusion occurs in small distance (inefficient)  For long distance communication animals use endocrine system and nervous system: o Endocrine system: chemical messengers travel from signaling cell to target cell carried by the circulatory system o Endocrine messengers are hormones o In the nervous system an electrical signal travels long distances through neurotransmitters (chemical messenger released from the neuron in synaptic cleft)  Exocrine communication: chemical messengers between individuals The biochemical basis of cell signaling:  Chemical messengers travel through the cytoplasm of signaling cell. When it approaches the target cell the messenger sends a signal goes through the lipid membrane to the cytoplasm General features of cell signaling:  Cells can move a hydrophilic chemical messenger through the lipid environment through gap junction o Gap junction are protein complexes that create pores between the cytoplasm of adjacent cells o Gap junctions are composed of cylindrical proteins build in groups of 4-6 o The hemichannel of the adjacent cells come together through a hollow tube, connecting the cells by the bridge o Thus chemical messengers don‟t have to go through aqueous environment  Direct communication by gap cells involves movement of ions between the cells (causing a change in membrane potential-coordinating a response)  Gap junctions can be opened and closed to regulate substances o Increase calcium and decreased intracellular pH can cause gap junctions to close  Animals use indirect cell signalling to send signals to distant cells that are not connected by jap junctions. There are three steps involved: 1. Release of chemical messenger to the extracellular environment 2. Transport of chemical messenger to the extracellular environment to target cell 3. Communication of the signal to target cell by receptor binding Indirect signaling systems for a continuum:  Autocrine, paracrine, neural, endocrine and exocrine communication differs largely in type of cell involved in messenger secretion and the way the messenger is transported to the target cell  The mechanism of releasing the messenger and the type of chemical messenger used is the very similar to all systems  Autocrine and paracrine communication, the chemical messenger diffuse through the extracellular fluid from signaling to target o thus affecting nearby target cells  Intracellular signaling occurs in short distances in nervous system through synapse: region where signaling cell and target cells are close together (can go through gap junction if cell-to cell) o neurotransmitters can carry a signal across a synapse by diffusing from signal cell to target cells (thus similar to paracrine communication) o neurons have the ability to produce electrical signals across long distances without cell degrading  endocrine system regulate the activities of distant cells, tissues and organs by sending chemical signals in blood through hormones (through circulatory system(  in exocrine communication, pheromone is released by one individual and travels to an external environment to cause an effect on a different individual  autocrine and paracrine communication are fast because chemical signals diffuse over small distances  nervous system is also fast due to propagation of neurons and diffusion of neurotransmitter across synapse  endocrine is slower because It transports hormones in the circulatory system  Only neurons act as secretory cells in nervous communication but many are involved in exocrine and endocrine  Some neurons release neurotransmitters to the circulatory system where a neurohormone, neurone acts like a hormone  Secretory cells of exocrine and endocrine tissue structures are called glands  Endocrine glands release hormones directly to the circulatory gland  exocrine glands release secretions into ducts that lead to the surfaces of the body o Exocrine glands that have pheromones are involved in animal to animal secretion and can also participate in locomotion digestion etc. o mucus secretions helps for locomotion, saliva helps with digestion the structure of the messenger determines the type of signaling mechanism:  hydrophobic messengers use can diffuse freely across cell membrane whereas hydrophilic cant.  There are 6 main classes of chemicals that participate in cellular signaling: peptides, steroids, amines, lipids, purines, steroids or amines Peptide Messengers:  Amino acids peptides and proteins act as signaling molecules o Amino acids act as neurotransmitters, peptides and proteins can act as autocrines, paracrine, hormones or pheromones  Peptide and protein messenger consist of two or more amino acids (peptide is smaller chains, protein larger chains) Peptide Messengers are realeased by exocytosis:  Peptides and protein messengers are synthesized by the ER o Peptides are packages into vesicles and stored o UNLIKE: Paracrine peptides, cytokines are synthesized for demand  Bacterium Clostridium botulinum is a protein that blocks the regulation of exocytosis of neurotransmitters travelling between nerves, preventing muscle contraction (used in Botox)  Peptide hormones are large inactive polypeptides called preprohormones o Preprohromones contain peptide hormones and is a signal sequence that targets the polypeptide for secretion o The signal sequence is cleaved from the preprohormone before it is packaged into vesicles forming a prohromone (inactive) o The vesicle has proteolytic enzymes that cut the prohromone into active hormone (ADH) Peptide messengers dissolve in extracellular fluids:  After it is released from the signaling cell, chemical messenger moves through the extracellular fluid to target cell  Hydrophilic chemical like peptides and proteins can be moved to the target cell by diffusion or by circulatory system  Peptide messengers are broken down by extracellular fluid or by proteolytic enzymes o The breakdown of the messenger is called half life Peptides bind to transmembrane receptors  Hydrophilic molecules (proteins and peptides) cant pass through the membrane of target cells so they bind to the transmembrane receptors o Extracellular portion of transmembrane receptor contains a ligand-binding domain o Ligand: any small molecule that binds to specific proteins, thus chemical messengers are ligands  Transmembrane receptors have a membrane spanning domain and intracellular domain o When a ligand binds to a ligand-binding domain of a transmembrane receptor, receptor changes shape and produces a signal across the cell o Transmembrane receptors activate the signal transduction pathway that cause the change in target cells Steroid Messengers:  Steroids come from cholesterol molecules  They act as paracrine and autocrine signals in some tissues and are important pheromones  The enzyme for steroid biosynthesis are located on the smooth ER or mitochondria  There are three major classes of steroids hormones on vertebrates o Mineralocorticods involved in regulating sodium uptake by the kidney and are important for fluid and electrolyte balance o Glucocorticoids: also called stress hormones, and increase the glucose production and break down proteins and increase release of fatty acids and regulate immune systems o Reproductibe hormone-production and regulate sex-specific characteristics and reproduction  The principle steroid in invertebrates are the ecdysteroids, the play an important role in regulation of molting in anthropoids  Since all steroids contain a carbon ring, some synthetic chemicals with similar structure can mimic or block the action of the hormone Steroids bind to carrier proteins:  Steroids can‟t pass through membranes and can‟t be stored in the cell, thus they are synthesized on demand  They can diffuse across the membrane into the extracellular fluid o Diffuse across short distances dissolved in extracellular fluids  Long distances transport requires carrier proteins-e.g. albumin, the principle carrier in proteins in vertebrate blood o Carrier proteins help hydrophobic chemical messenger dissolve in aqueous solutions by using hydrophobic messengers  Hydrophobic messengers bind to carrier proteins and result in an equilibrium between bound messengers o If amount of free messenger increase equilibrium shift to the right, increasing the amount of messenger bound to the protein  When a signaling cell releases a chemical messenger into the extracellular fluid, the free concentration of the messenger is in high concentration and thus will bind to the carrier protein  both free and bound messengers travel in the circulatory system to target cell o At the target cell the free messenger diffuse to cell and bind to the receptor o Thus producing a low concentration of free messenger outside causing the bound messenger to dissociate from carrier protein and deliver it to the target cell Steroids bind to intracellular receptors:  Lipophilic steroid can easily cross the membrane of the targeted cells and bind to the transmembrane receptors or the receptors in the cell  The intracellular steroid receptors act as transcription factors (controlling gene expression) o Thus there is a lag time between the binding of messenger and the observation o However when you bind a steroid messenger to a transmembrane receptor it activates the cytoplasmic transduction pathway causing a rapid non0genomic effect (no change in translation or transcription) Biogenic Amines:  Amines: chemicals that possess an anime attached to a carbon  Biogenic amine: amines that function in cellular signalling  Catecholamine (dopamine, norepinephrine and epinephrine) are synthesized from amino acid tyrosine  Dopamine: found in animal taxa and is a neurotransmitter  Norepinephrine and epinephrine: known only from vertebrates and act as neurotransmitters, paracrines and hormones  Octaopamine and tyramine are important neurotransmitters for invertebrates  Thyroid hormones are synthesize from a polypeptide containing amino tyrosine  Serotonin: synthesized from amino acid trypophran is a neurotransmitter for all animal taxa  Melatonin: synthesized from the amino acid tryophan and acts as a neurotransmitter and a hormone o plays an important role in regulating wake cycles and seasonal rhythms o for vertebrates it is involved regulation of activity patterns  histamine: synthesized from the amino acid histidine o functions as a neurotransmitter and a paracrine signaling molecule in vertebrates and invertebrates o Histamine plays an important role in immune responses and allergic reactions  Acetylcholine: neurotransmitters found in animals and is synthesized from choline, amine and a acetyl CoA o Neurotransmitter at the neuromuscular junction of vertebrates because its important junction for vertebrates  Most biogenic amines are hydrophilic and are packaged into vesicles and released in the extracellular fluid by exocytosis Thyroid hormones diffuse across the membrane:  Thyroid hormone begins when enzyme iodinate adds more iodine molecules to tyrosine residue in the protein thyroglobulin  Is a tyrosine is iodinated once you produce MIT, if twice iodinated your produce DIT  T3 and T4 are called thyroid hormones, and are apart of the thyroglobulin protein which is packaged into vesicles o The vesicles fuse within the lysosomes (organelle contains proteinases) o Proteinases digest thyroglobulin and releases the T3 and T4  Thyroid hormones are hydrophobic and can diffuse out of the lysosomes across the plasma membrane of the signaling cell Thyroid messengers are hydrophobic messengers:  Hydrophobic thyroid molecules are carried to the blood bound to a carrier protein and are bound to an intracellular receptor in target cell o The thyroid receptor acts a s a transcription fact when bound to thyroid hormone altering transcription of genes  Thyroid hormones act more like a steroid hormone than a peptide hormone Other classes of messengers: Eicasanoids are lipid messengers  Lipids called eicosanoids can act as neurotransmitters and paracrine chemical messengers o Hydrophobic eicasonoids diffuse out of the membrane of signaling cell and diffuse to the target cell  They also have very short half-life in extracellular fluids o Thus they can‟t be transported across long distances and cant act as hormones  Eicasonoids synthesis begins either the lipoxygenase pathway which produces leukotrines and lipoxins or the cyclooxygenase pathway that produces prostaglandins, prostacyclins and thromboxanes o Pain killers work by blocking prostaglandins synthesis  Eicasonoids also function as neurotransmitters Nitric oxide is a gaseous chemical messenger  Only three gases are known to act as chemical messengers in animals: nitric oxide, carbon monoxide and hydrogen sulfide o Nitric oxide: first gas identified as a chemical messenger o Nitric oxide is produced by enzyme NOS, which catalyzes the reaction of the amino acid arginine with oxygen to produce nitric oxide and citrulline  Nitric oxide has a short half-life and acts as a paracrine messenger or a neurotransmitter  Nitric oxide plays a critical role in regulating functions because it is a vasodilator o Cause smooth muscle around blood vessels to relax and increases the diameter to allow more blood flow  Importantly nitric oxide is important for paracrine communication in the immune system  Since it‟s a gas it can diffuse across the cell membrane towards target cells  An important action it does is that it activates the enzyme guanylate cyclase o Guanylate cyclase catalyzes formation of cyclic cGMP activates kinase  cGMP is removed by PDE which terminates nitric acid-causing cells to relax (vasodilation) Purines can act as neurotransmitters and paracrines:  purines act as neurotransmitters, neurohormones and paracrines  neuromodulator is a cellular signaling molecule that alters activity of other signaling molecules  purines are released from signaling cells by a variety of mechanism o purines can be packaged into secretory vesicles and released by exocytosis o purines that bind to membrane receptors are purinergic receptors Communication of the signal to the target cell:  when a ligand binds to a receptor this changes the shape and send signal to target cell  hydrophilic ligand bind to transmembrane proteins and change in receptor allow the ligand to cross  hydrophobic ligand can either bind to the receptor or pass through the membrane and bind to the intracellular receptors Ligand-receptor interactions are specific:  ligand receptor interactions are particular to the shape of the ligand  chemicals that bind to and activate receptors are called agonist  chemicals that bind to but do not activate the receptors are called antagonist Receptors have several domains:  Ligand-binding domains contain the binding site for the chemical messenger  The remaining domain plays a functional role by interacting with signal transduction molecules in the cell  The structure of the ligand-binding domain determines the nature of the receptor effects  For many receptors you can construct recombinant proteins with the ligand-binding domain of one receptor and function domains of another protein o The type of functional domain in the recombinant protein determine the nature of response of the target cell A ligand may bind to more than one receptor  Receptor isoforms share similar ligand-binding domains, but differ in functional domains o Isoforms allow the same signaling molecule to have different effects Ligand-receptor binding obeys the law o
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