Lecture 12 - Inter-Organ Communication PDF

Inter-organ communication Dr. Ardina Grüber Nanyang Technological University School of Biological Sciences Division of Structural Biology and Biochemistry Singapore 637551...

Inter-organ communication Dr. Ardina Grüber Nanyang Technological University School of Biological Sciences Division of Structural Biology and Biochemistry Singapore 637551 email: [email protected]  Metabolic interactions among the major fuel-metabolizing organs The major fuel metabolites imported and exported by each organ are shown, along with the fuel stores and major energy pathways that take place in each organ. Lipid-derived metabolites are highlighted in yellow; carbohydrate-derived metabolites are highlighted in blue. Copyright ©2019, 2016, 2013 Pearson Education Inc. All rights reserved  Profiles of the major vertebrate organs in fuel metabolism ~ require high art of energy can work acrobia/ anaerobic works decobia ~ only - no rest State Copyright ©2019, 2016, 2013 Pearson Education Inc. All rights reserved  cell body Coordination of Fuel Metabolism Two systems coordinate communication throughout the body: the nervous system and axou tips - nevotransmitters the endocrine system (a) In neuronal signalling, electrical signals originate in the cell body of a neuron and travel very rapidly over long distances to the axon tip, where neurotransmitters are released and diffuse to the target cell & (micrometres range). travel short distances travel long distances ~ (b) In the endocrine system, hormones are secreted into the bloodstream, which carries them throughout the body to target tissues that may be a meter or more away from the secreting cell. hormones Both neurotransmitters and hormones interact with specific receptors on or in their target cells, triggering responses. secreted Lehninger Pricniples of Biochemistry, Fifth Edition © 2008 W.H. Freeman and Company  Neurotransmitters and Neurohormones Neurones (nerve cells) contact target cells at synapses. At synapses, neurones often secrete chemical signals called neurotransmitters* that diffuse a short distance to bind to receptors on the target cell. Neurotransmitters play a role in sensation, memory, cognition and movement. longer than neurotransmitters ~ can travel slightly Neurohormones - are a class of hormones that small proteins originate from neurons from brain and diffuse through the blood stream. g. oxytocin vasopresin e. & * Glutamate, γ –aminobutyric acid (GABA), acetylcholine, serotonin and glycine; Classic neurotransmitters) Peptide molecules: substance P, opoide and somatostatin Nitric oxide (gas]  Hormonal Regulation all influence processes positively/negatively on can 1. Growth and differentiation of cells, tissues, and steroid organs hormones include cell proliferation, embryonic development, and sexual differentiation (time requiring processes involving proteins de novo synthesis). mainly steroid hormones which function via ~ majority influence these transcription regulation are active in this field. pathways indirectly not directly influency i main enzymes doing 2. Metabolic pathway metabolic regulation requires rapidly acting synthesis or a mechanisms. many of the hormones involved therefore regulate interconversion of enzymes. 3. Digestive processes are usually regulated by locally acting peptides (paracrine), but mediators, biogenic amines, and neuropeptides are also involved. 4. Maintenance of ion concentrations (homeostasis) Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme  Hormonal Regulation hydrophobic character carrier H interact o bird to to be receptor to allow it transported to target cell transported to kidney > hydrophilic hormones can travel in circulatory need system & don't to be combined o liver Kidney any transporter converted to metabolites Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme  Hormonal Regulation Mammals have several classes of hormones which differ by their chemical structures and modes of action. & coupds funch as neurotransmitters ~ water soluble , hormones norepinephrine -small molecule gas  Hormonal Regulation of Fuel Metabolism Fundamentals of Biochemistry, Life at the Molecular Level by Voet,Voet, Pratt (Wiley, 2008) i hormones influence many diff p. & indirectly influence metabolic pathway  Cytokines Regulation of Fuel Metabolism Cytokines (signaling molecules) - large group of proteins, peptides or glycoproteins that are secreted by specific cells of immune system. Many signaling molecules produced by metabolic organs has been identified and named as ❖ hepatokines (liver) ❖ myokines (muscle) ❖ adipokines (white adipose tissues, WAT) and ❖ batokines (brown adipose tissues, BAT) The secretion of these signaling molecules varies according to the metabolic status of the body. They respond to: ❖ fasting and feeding cycles ❖ the circadian rhythm ❖ cold exposure and The Impact of Organokines on Insulin Resistance, Inflammation, and Atherosclerosis, ❖ exercise Endocrinol Metab 2016;31:1-6  Cytokine Regulation of Fuel Metabolism Don't need to memorise all i names of cytokines Cytokines can regulate cellular activity in a coordinated interactive way due to the following attributes: & originated Pleiotrophy - one cytokine has many different in bones functions. can initiate diff reactions Redundancy - several different cytokines can mediate the same or similar functions. Synergism - occurs when the combined effect of two cytokines on cellular activity is greater than the additive effects of individual cytokines. Antagonism - the effects of one cytokine inhibits or offsets the effects of another cytokine. Shi J, Fan J, Su Q and Yang Z (2019) Cytokines and Abnormal Glucose and Lipid Metabolism. Front. Endocrinol. 10:703. doi: 10.3389/fendo.2019.00703  Hormones - class of proteins that act as signaling molecules. Hormones are secreted by a given tissue and are used to communicate between organs [hormones) higher in order to trigger integrative are than [cytokines] responses to specific stimuli. Cytokines - class of small proteins that can be produced by a broad variety of cells and act as signaling molecules. In circulation, cytokines are usually found in smaller cytokines & their receptor concentration than hormones. exhibit very high offinity does for elo : [cytokines] not have to be high  Hormonal/Cytokine Regulation of Fuel Metabolism Hormones and cytokines can be classified by the way they get from the point of their release to their target tissue: molecules ~ long-distance hormones/signaling Endocrine (from the Greek endon, “within,” and krinein, “to release”) hormones are released into the blood and carried to target cells throughout the body (insulin is an example). Paracrine hormones are released into the extracellular space locallators/ locally-acting S and diffuse to neighboring target cells (eicosanoids). Autocrine hormones are released by and affect the same cell, binding to receptors on the cell surface (eicosanoids, interleukin-1). Local regulators (paracrine and autocrine) = Short Distance Chemical Signals What are these events by which the binding of a chemical messenger to a receptor causes the cell to respond to the messenger?  Signal transduction pathways The interaction of messenger with receptor causes a change in the conformation of the receptor - receptor activation. This activation is the first step leading to the cell’s ultimate response. The sequences of events between receptor activation and the responses are termed signal transduction pathways. These responses can take the form of changes in the : ❖ permeability, transport properties, or electrical state of the cell’s plasma membrane; ❖ cell’s metabolism; ❖ cell’s secretory activity; ❖ cell’s rate of proliferation and differentiation; and first messenger ❖ cell’s contractile activity.  The important question is: How does receptor activation influence the cell’s internal proteins, which are usually critical for the response but may be located far from the receptor? Signal transduction pathways differ for lipid- soluble and lipid-insoluble messengers. The receptors for these two broad chemical classes of messenger are in different locations – lipid-soluble inside the cell and lipid-insoluble in the plasma membrane of the cell.  bind to receptor Mechanism of action of lipophilic hormones in nucleus 2 pathways slightly different bind to receptor in cutoplasm into diffuse nucleus receptor binding in nucleus homodiment heterodiver bird to control https://opentextbc.ca/anatomyandphysiology/chapter/17-2-hormones/ elements in promoter region of specific geredits influence transcript they Glucocorticoids - binding to specific , act as transcript? factors cytoplasmic receptor Vitamin D, retinoic acid, thyroid hormone – bird to diffusing across the plasma membrane & nucleus to nucleus receptors Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme  Mechanism of action of lipophilic hormones Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme  mainly used by neurotransmitters Diff classes of receptors ~ 7) x-helix span e membe Mechanism of action of hydrophilic ligand-gated ion channels 7 times 1 x-helix spanning hormones e memb" one time confe A ~ conformational A activated activated https://opentextbc.ca/anatomyandphysiology/chapter/17-2-hormones/ Act within I cell 1-Helix receptor: ❖ Insulins, growth factors, and cytokines Ion Channel receptors: ❖ neurotransmitters such as acetylcholine and gamma-aminobutyric acid (GABA) Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme Insulin signalling system: 1-helix receptors Not yet fully elucidated - clearly highly complex. Upon binding insulin, the insulin receptor autophosphorylates itself at several Tyr residues and then Tyr-phosphorylates its target proteins, thereby activating several signaling pathways that control a diverse array of effects. By activating multiple pathways, a hormone such as insulin can trigger a variety of physiological effects that would not be possible in a one hormone - one target regulatory system.  Signal transduction by G proteins: 7-Helix receptors outsidecell bind to : receptor molecules specific signaling - G-protein coupled receptors other cytosolic face bird to : that are located in cytoplasm Class 1A – rhodopsin like GPCRs can be grouped into 6 (A-F) classes ❖ Glucagone - Class B based on sequence homology and functional ❖ Epinephrine - β-adrenergic receptors similarity. α2-adrenergic receptors  a signaling moleculebon mode of action of o proteins causing in i a conformational receptor A connected to plasma membrane Signal transduction by G proteins causing interaction befor & a protein receptor B X subunit subunit -O submit displaced ~ opposite acti of is a subunit binding don't have tolearnI action of all causinga protein to dissociate = G protein subunits just understand epinephrine insulin signal pathways & -subunit to from receptor fro & 0 subunit glucagon , , subunits dissociate B involved & action of a /B ↓ protein both subunits are now activated & able to influence physiological processes  Different types of second messengers specificby eat ~ thatinitiate intracellular chemical signals their concentration is regulated by hormones, neurotransmitters, and other extracellular signals they arise from easily available substrates and only have a short half-life the most important second messengers are ❖ cAMP, ❖ cGMP, ❖ Ca2+, ❖ inositol triphosphate (InsP3), ❖ diacylglycerol (DAG), and ❖ nitrogen monoxide (NO).  Mechanism of Action for cyclic AMP The nucleotide cAMP is synthesized by membrane-bound adenylate cyclases The degradation of cAMP to AMP is catalyzed by phosphodiesterases inhibits Phosphodiesterases are inhibited by methylxanthines such as caffeine deactivate of cleared CAMP Adenylate cyclase activity is regulated by G activated proteins (Gs and Gi)* Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme  Mechanism of Action for Ca2+ ions Captions ③ small P that binds 4 Calcium level is a signaling substance The concentration of Ca2+ ions in the cytoplasm is normally very low (10- D ② 100nM) ① [a2t ATP Specific signals can trigger a sudden pumps in a increase in the cytoplasmic Ca2+ level PM & in ER membrane & to 500-1000nM by opening Ca2+ ③ Cal Not - jou from ER & undergoes conformational A channels in the plasma membrane or & ④ other o modulates in the membranes of the endoplasmic & pumps to interactoo a & e properties cazt-binding cast ion p that all influence I pumps & or sarcoplasmic reticulum. keeps ((art) positively from outside ↑[at( low of all /. calmodulin e q. , troponin ( of membrane allowingT influx of caltions into I cell Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme The biochemical effects of Ca2+ in the cytoplasm are mediated by special Ca2+ - binding proteins-calcium sensors  Mechanism of Action for InsP3 and DAG hydrophilic Type Gq proteins activate phospholipase C PLC creates two second messengers: involve in ❖ inositol 1,4,5-trisphosphate phosphate PLL signal cascade ❖ diacylglycerol cleares phospholipid activated InsP3 migrates to the ER, where it opens (in membrane) Ca2+ channels that allow Ca2+ to flow into the cytoplasm water-soluble& migrates DAG remains in the membrane, Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme to ER where it activates type C protein kinases The changing levels of specific hormones regulate specific cellular processes, but what regulates the level of each hormone?  Hormone Release Is Regulated by a Hierarchy of Neuronal and Hormonal Signals The central nervous system receives input from many internal and external and orchestrates the production of appropriate hormonal signals by the endocrine tissues. Hypothalamus - the coordination center of the endocrine system (receives and integrates messages from the central nervous system) & produces releasing factors a passes to pituitary gland The pituitary gland has two functionally distinct parts: The posterior pituitary contains the axonal endings of many hormones short peptide neurons that originate in the hypothalamus. neurons pale vasopregin) which moves to axon Coxytociu & endings intoe & is to nerve pituitary The anterior pituitary responds to hypothalamic hormones stored granules in secret a for carried in the blood, producing tropic hormones, or tropins e siguals released to be (from the Greek tropos, “turn”). they activate I next rank of endocrine glands , & they secrete in blood their specific hormones to target call receptors Biochemistry, Sixth Edition Mary K. Campbell, Shawn O. Farrell  Hierarchical nature of hormone Hierarchicalaction in vertebrates Lehninger Pricniples of Biochemistry, Fifth Edition © 2008 W.H. Freeman and Company  Cascade of hormone release following central nervous system input to the hypothalamus At each level of a hormonal cascade, feedback inhibition of earlier steps in the cascade is possible; an unnecessarily elevated level of the ultimate hormone or of one of the intermediate hormones inhibits the release of earlier hormones in the cascade. These feedback mechanisms accomplish the same end as those that limit the output of a biosynthetic pathway: a product is synthesized (or released) only until the necessary concentration is reached. Lehninger Pricniples of Biochemistry, Fifth Edition © 2008 W.H. Freeman and Company