Receptors Functions and Signal Transduction L1- L2

Faisal I. Mohammed, MD, PhD

University of Jordan

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 Signal Transduction (Regulation of cellular machinery) Extracellular regulators: nervous, endocrine, paracrine and autocrine Steroids: Their Signal Transduction And Mechanism Of Action Microcirculation: Capillary Structure; Fluid Filtration (Forces) & Reabsorption - Starling Law Of Capillary Exchange - Lymphatic System Action Potential: Cardiac Action Potential (Fast Response AP) Vs Slow Response AP (The Pacemaker Concept)

20-21

Dr. Faisal

910-915

886-891

22-23

Dr. Faisal 934-936 962-963 Dr. Faisal 949 954 Dr. Faisal 181-190

910-912 940-941 926-927 931 177-186

24 25-26

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

Objectives
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
n

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Intercellular Communication
Endocrine
Cell
Target Cell

Hormone

Blood

Hormone
Target Cell

Neuroendocrine

Neuron

Blood Hormone Hormone

Paracrine

Cell

Interstitial Fluid

Target Cell

Hormone

Hormone

Autocrine

Cell

Hormone

Interstitial Fluid

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GAS MOLECULE

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Endocrine Glands and Hormones

Neurohormone: q Specialized neurons that secrete chemicals into the blood rather than synaptic cleft. n Chemical secreted is called neurohormone. Hormones: q Affect metabolism of target organs. n Help regulate total body metabolism, growth, and reproduction.

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Classes of Hormones

Peptide & Protein Hormones Steroid Hormones Amine Hormones Gas Nitric Oxide (NO)

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Hormone types q Circulating circulate in blood throughout body q Local hormones act locally

Paracrine act on neighboring cells n Autocrine act on the same cell that secreted them
n

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Chemical classes of hormones

qLipid-soluble use transport proteins q Steroid: Lipids derived from cholesterol.
q Are

lipophilic hormones. qTestosterone. qEstradiol. qCortisol. qProgesterone.

q Thyroid q Nitric oxide (NO)

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Chemical classes of hormones cont

qWater-soluble circulate in free form qAmines: q Hormones derived from tyrosine and tryptophan. qPolypeptides and proteins: q Polypeptides:
q Chains

of < 100 amino acids in length. qADH.

q Protein hormones:
q Polypeptide

chains with > 100 amino acids. q Growth hormone.

qEicosanoid (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 and subunits ( is common and is specific) 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. Preprohormone: q Prohormone derived from larger precursor molecule. n Preproinsulin. 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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Peptide & Protein Hormones

Gland/Tissue
Hypothalamus

Hormones
n TRH,

Gland/Tissue
Placenta

Hormones
n HCG,

GnRH, CRH GHRH, Somatostatin, TSH, FSH, LH, PRL, GH ADH

HCS or HPL

Anterior pituitary

n ACTH,

Kidney

n Renin

Posterior pituitary Thyroid Pancreas Liver Parathyroid

n Oxytocin,

Heart G.I. tract

n ANP

n Calcitonin

n Gastrin,

n Insulin,Glucagon,

CCK, Secretin, GIP, Somatostatin

Somatostatin
n Somatomedin

C (IGF-1)

Adipocyte Adrenal medulla

n Leptin

n PTH

n Norepinephrine,

epinephrine
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Synthesis and secretion of peptide hormones

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Amine Hormones

Gland/Tissue Hypothalamus Thyroid Adrenal medulla

Hormones
n Dopamine

n T3,

T4 EPI

n NE,

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Synthesis of Amine Hormones

tyrosine hydroxylase dopa decarboxylase Dopaminergic Neurons

Tyrosine

L-Dopa

Dopamine

dopamine hydroxylase Adrenergic Norepinephrine Neurons phenylethanolamineN-methyltransferase

Epinephrine
Adrenal Glands

Thyroid Hormones
Thyroid Gland

Steroid Hormones

Gland/Tissue Hormones
n Cortisol, Aldosterone,

Adrenal Cortex Testes Ovaries Corpus Luteum Placenta Kidney

Androgens n Testosterone
n Estrogens,

Progesterone n Estrogens, Progesterone

n Estrogens,

Progesterone n 1,25-Dihydroxycholecalciferol (calcitriol)

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Hormone Activity
n

Hormones affect only specific target tissues with specific receptors Receptors are dynamic and constantly synthesized and broken down
q q

Down-regulation 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. 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 n

[Hormone] in blood reflects the rate of secretion. Half-life: q Time required for the blood [hormone] to be reduced to reference level. n Minutes to days. Normal tissue responses are produced only when [hormone] are present within physiological range. 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. 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 Hormones 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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Membrane receptors membrane Glycoprotein Intracellular receptors Cytosol or nuclei DNA binding protein

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1. membrane receptors
(1) Ligand-gate ion channels type (cyclic receptor) ligandreceptorion channel open or close

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(2) G Protein-Coupled Receptors

1) 7-helices transmembrane receptor

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Oligosaccharide
unit

Cytosolic side

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2) G protein (Guanylate binding protein)

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 (, , subunit) bound to GDP when exchanged to GTP activate -subunit n -subunit carries GTPase activity, binding and hydrolysis of GTP.

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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 n n n n

highly specificity highly affinity saturation reversible binding special function model
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Receptor Types
n

Channel-linked receptors
q

Ionotropic Protein kinases phosphorylation Neurotrophins Metabotropic Activation by cell-permeant signals ~

Enzyme-linked receptors
q q

G-protein-coupled receptors
q

Intracellular receptors
q

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