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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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