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Receptors Functions and Signal Transduction L1- L2
Faisal I. Mohammed, MD, PhD
Introduction to Physiology (0501110) Summer 2012
Subject
Lecture No.
Lecturer Pages in the 11th edition. textbook
Pages in the 12th edition textbook
Receptors: types and adaptation - Membrane or intracellular
- Ion channels
- G-protein
- Enzyme linked
- Intracellular - Second messengers
- cAMP and cGMP, Phospholipid
- Calcium calmodulin and IRS
20-21 Dr. Faisal 910-915 886-891
Signal Transduction (Regulation of cellular machinery) Extracellular regulators: nervous, endocrine, paracrine and autocrine
22-23 Dr. Faisal 934-936 962-963
910-912 940-941
Steroids: Their Signal Transduction And Mechanism Of Action
24 Dr. Faisal 949 954
926-927 931
Microcirculation: Capillary Structure; Fluid Filtration (Forces) & Reabsorption
- Starling Law Of Capillary Exchange
- Lymphatic System
25-26 Dr. Faisal 181-190 177-186
Action Potential: Cardiac Action Potential (Fast Response AP) Vs Slow Response AP (The Pacemaker Concept)
27-28 Dr. Faisal (FM)
103-106 116-121
101-104 115-120
Textbook: Guyton Medical Textbook of Physiology By: Guyton and Hall 12th edition
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Objectives
n Define first messenger (Hormones) n List hormone types n Describe receptor types n Outline the hormone receptors interactions n Describe second messenger mechanism of action n List second messengers
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Intercellular Communication Cell Target Cell
Cell
Cell Target Cell
Target Cell Neuron
Hormone
Hormone
Hormone Hormone
Hormone
Hormone
Hormone
Endocrine
Paracrine
Autocrine
Blood Neuroendocrine
Blood
Interstitial Fluid
Interstitial Fluid
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GAS MOLECULE
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Endocrine Glands and Hormones
n Neurohormone: q Specialized neurons that secrete chemicals into the blood
rather than synaptic cleft. n Chemical secreted is called neurohormone.
n Hormones: q Affect metabolism of target organs.
n Help regulate total body metabolism, growth, and reproduction.
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• Peptide & Protein Hormones
• Steroid Hormones
• Amine Hormones
• Gas – Nitric Oxide (NO)
Classes of Hormones
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n Hormone types q Circulating – circulate in blood throughout
body q Local hormones – act locally
n Paracrine – act on neighboring cells n Autocrine – act on the same cell that
secreted them
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Chemical classes of hormones
q Lipid-soluble – use transport proteins q Steroid: Lipids derived from cholesterol.
q Are lipophilic hormones. q Testosterone. q Estradiol. q Cortisol. q Progesterone.
q Thyroid q Nitric oxide (NO)
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Chemical classes of hormones …cont
q Water-soluble – circulate in “free” form q Amines: q Hormones derived from tyrosine and tryptophan.
q Polypeptides and proteins: q Polypeptides:
q Chains of < 100 amino acids in length. q ADH.
q Protein hormones: q Polypeptide chains with > 100 amino acids. q Growth hormone.
q Eicosanoid (prostaglandins)
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Chemical Classification of Hormones …cont n Glycoproteins:
q Long polypeptides (>100) bound to 1 or more carbohydrate (CHO) groups. n FSH and LH, TSH and hCG (human chorionic
gonadotropin) They have α and β subunits (α is common and β is
specific) n Hormones can also be divided into:
q Polar: n H20 soluble.
q Nonpolar (lipophilic): n H20 insoluble.
q Can gain entry into target cells. q Steroid hormones and T4.
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Prohormones and Prehormones n Prohormone:
q Precursor is a longer chained polypeptide that is cut and spliced together to make the hormone. n Proinsulin.
n Preprohormone: q Prohormone derived from larger precursor molecule.
n Preproinsulin. n Prehormone:
q Molecules secreted by endocrine glands that are inactive until changed into hormones by target cells. n T4 converted to T3.
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Hypothalamus Anterior pituitary Posterior pituitary
Thyroid
Pancreas
Liver
Parathyroid
n TRH, GnRH, CRH GHRH, Somatostatin, n ACTH, TSH, FSH, LH, PRL, GH
n Oxytocin, ADH
n Calcitonin
n Insulin,Glucagon, Somatostatin
n Somatomedin C (IGF-1)
n PTH
Placenta
Kidney
Heart
G.I. tract
Adipocyte
Adrenal medulla
n HCG, HCS or HPL
n Renin
n ANP
n Gastrin, CCK, Secretin, GIP, Somatostatin
n Leptin
n Norepinephrine, epinephrine
Gland/Tissue Hormones Gland/Tissue Hormones
Peptide & Protein Hormones
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Synthesis and secretion of peptide hormones
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Amine Hormones
Hypothalamus Thyroid Adrenal medulla
n Dopamine
n T3, T4
n NE, EPI
Gland/Tissue Hormones
Tyrosine
L-Dopa
Dopamine
tyrosine hydroxylase
Norepinephrine
dopa decarboxylase
dopamine β -hydroxylase
Dopaminergic Neurons
Thyroid Hormones
Adrenergic Neurons
Epinephrine
phenylethanolamine-N-methyltransferase
Thyroid Gland Adrenal Glands
Synthesis of Amine Hormones
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Adrenal Cortex Testes Ovaries Corpus Luteum Placenta Kidney
n Cortisol, Aldosterone, Androgens n Testosterone
n Estrogens, Progesterone n Estrogens, Progesterone
n Estrogens, Progesterone n 1,25-Dihydroxycholecalciferol (calcitriol)
Gland/Tissue Hormones
Steroid Hormones
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Hormone Activity
n Hormones affect only specific target tissues with specific receptors
n Receptors are dynamic and constantly synthesized and broken down q Down-regulation q Up-regulation
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Effects of [Hormone] on Tissue Response
n Priming effect (upregulation): q Increase number of receptors formed on target cells in
response to particular hormone. q Greater response by the target cell.
n Desensitization (downregulation): q Prolonged exposure to high [polypeptide hormone].
n Subsequent exposure to the same [hormone] produces less response. q Decrease in number of receptors on target cells.
§ Insulin in adipose cells. q Pulsatile secretion may prevent downregulation.
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Effects of [Hormone] on Tissue Response
n [Hormone] in blood reflects the rate of secretion. n Half-life:
q Time required for the blood [hormone] to be reduced to ½ reference level. n Minutes to days.
n Normal tissue responses are produced only when [hormone] are present within physiological range.
n Varying [hormone] within normal, physiological range can affect the responsiveness of target cells.
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Mechanisms of Hormone Action n Hormones of same chemical class have similar mechanisms
of action. q Similarities include:
n Location of cellular receptor proteins depends on the chemical nature of the hormone.
n Events that occur in the target cells. n To respond to a hormone:
q Target cell must have specific receptors for that hormone (specificity). n Hormones exhibit:
q Affinity (bind to receptors with high bond strength). q Saturation (low capacity of receptors).
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Mechanisms of Hormone Action
± Response depends on both hormone and target cell ± Lipid-soluble hormones bind to receptors inside target
cells ± Water-soluble hormones bind to receptors on the plasma
membrane ± Activates second messenger system ± Amplification of original small signal
± Responsiveness of target cell depends on ± Hormone’s concentration ± Abundance of target cell receptors
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Receptor
Receptors are specific membrane proteins, which are able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules.
Glycoprotein or Lipoprotein
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ligand
A small molecule that binds specifically to a larger one; for example, a hormone is the ligand for its specific protein receptor.
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n Membrane receptors
membrane
Glycoprotein
n Intracellular receptors
Cytosol or nuclei
DNA binding protein
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(1) Ligand-gate ion channels type
(cyclic receptor)
ligand→receptor→ion channel open or close
1. membrane receptors
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1) 7-helices transmembrane receptor
(2) G Protein-Coupled Receptors
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Cytosolic side
Oligosaccharide unit
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n G protein refers to any protein which binds to GDP or GTP and act as signal transduction. n G proteins consist of three different subunits (α, β, γ-subunit) bound to GDP when exchanged to GTP activate α-subunit n α-subunit carries GTPase activity, binding and hydrolysis of GTP.
2) G protein (Guanylate binding protein)
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Neurotransmitter ���“Second Messenger” System
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cAMP
ATP
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- Pathway of G protein linked receptor
H R G protein Es
secondary messeger
Protein kinase
Phophorylation of Es or functional protein
Biological effect
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Properties of binding of H and R
n highly specificity
n highly affinity
n saturation
n reversible binding
n special function model
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Receptor Types n Channel-linked receptors
q Ionotropic n Enzyme-linked receptors
q Protein kinases à phosphorylation q Neurotrophins
n G-protein-coupled receptors q Metabotropic
n Intracellular receptors q Activation by cell-permeant signals ~
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