University:
Kentucky State University
Course:
CHE 315 | Biochemistry
Academic year:

2022
Views:

29

Pages:

71
Author:

Athena Harrison

Receptors Functions and Signal Transduction L1- L2 1 Objectives       Define first messenger (Hormones) List hormone types Describe receptor types Outline the hormone receptors interactions Describe second messenger mechanism of action List second messengers 2 3 4 Fig. 03.03 5 Overview of Signal Transduction A. Definitions Signaling: Cell-cell communication via signals. Signal transduction: Process of converting extracellular signals into intra-cellular responses. Ligand: The signaling molecule. Receptors: Bind specific ligands. Transmit signals to intracellular targets. Different receptors can respond differently to the same ligand. B. Components involved in signaling: Ligands Receptors Intracellular Signaling Proteins Intermediary Proteins Enzymes Second Messengers Target Proteins 6 Inactivating Proteins Overview of Signal Transduction 7 Intercellular Communication Endocrine Cell Hormone Neuroendocrine Target Cell Blood Neuron Hormone Target Cell Blood Hormone Paracrine Cell Hormone Interstitial Fluid Hormone Autocrine Hormone Cell Hormone Target Cell Interstitial Fluid Endocrine Glands and Hormones   Neurohormone:  Specialized neurons that secrete chemicals into the blood rather than synaptic cleft.  Chemical secreted is called neurohormone. Hormones:  Affect metabolism of target organs.  Help regulate total body metabolism, growth, and reproduction. 9 10 Classes of Hormones • Peptide & Protein Hormones • Steroid Hormones • Amine Hormones •Gas – Nitric Oxide (NO) 11  Hormone types  Circulating – circulate in blood throughout body  Local hormones – act locally   Paracrine – act on neighboring cells Autocrine – act on the same cell that secreted them 12 13 GAS MOLECULE 14 15 16 Chemical classes of hormones  Lipid-soluble – use transport proteins  Steroid: Lipids derived from cholesterol.  Are lipophilic hormones. Testosterone. Estradiol. Cortisol. Progesterone.  Thyroid  Nitric oxide (NO) 17 Chemical classes of hormones …cont  Water-soluble – circulate in “free” form Amines:  Hormones derived from tyrosine and tryptophan.  NE, Epi, T4 (lipid soluble) Polypeptides and proteins:  Polypeptides:  Chains of < 100 amino acids in length. ADH.  Protein hormones: Polypeptide chains with > 100 amino acids.  Growth hormone.  Eicosanoid (prostaglandins) 18 Chemical Classification of Hormones …cont   Glycoproteins:  Long polypeptides (>100) bound to 1 or more carbohydrate (CHO) groups.  FSH and LH, TSH and hCG (human chorionic gonadotropin) They have α and β subunits (α is common and β is specific) Hormones can also be divided into:  Polar:  H20 soluble.  Nonpolar (lipophilic):  H20 insoluble.  Can gain entry into target cells.  Steroid hormones and T4. 19 Prohormones and Prehormones    Prohormone:  Precursor is a longer chained polypeptide that is cut and spliced together to make the hormone.  Proinsulin. Preprohormone:  Prohormone derived from larger precursor molecule.  Preproinsulin. Prehormone:  Molecules secreted by endocrine glands that are inactive until changed into hormones by target cells.  T4 converted to T3. 20 Peptide & Protein Hormones Gland/Tissue Hormones Hypothalamus  Anterior pituitary  Posterior pituitary Gland/Tissue Hormones TRH, GnRH, CRH GHRH, Somatostatin, Placenta  HCG, HCS or HPL ACTH, TSH, FSH, LH, PRL, GH Kidney  Renin  Oxytocin, ADH Heart  ANP Thyroid  Calcitonin G.I. tract  Pancreas  Liver  Somatomedin C (IGF-1) Adipocyte Parathyroid  PTH Adrenal medulla Insulin,Glucagon, Somatostatin Gastrin, CCK, Secretin, GIP, Somatostatin  Leptin Norepinephrine, epinephrine  21 Synthesis and secretion of peptide hormones 22 Amine Hormones Gland/Tissue Hormones Hypothalamus  Dopamine Thyroid  T3, T4 Adrenal medulla  NE, EPI 23 Synthesis of Amine Hormones tyrosine hydroxylase Tyrosine L-Dopa dopa decarboxylase Dopaminergic Neurons Dopamine dopamine  hydroxylase Adrenergic Norepinephrine Neurons phenylethanolamineN-methyltransferase Epinephrine Adrenal Glands Thyroid Hormones Thyroid Gland Steroid Hormones Hormones Gland/Tissue Adrenal Cortex Testes Cortisol, Aldosterone, Androgens  Testosterone  Estrogens, Progesterone  Estrogens, Progesterone Ovaries Corpus Luteum  Placenta Kidney  Estrogens, Progesterone  1,25-Dihydroxycholecalciferol (calcitriol) 25 Chemical classification of hormones 26 Hormone Activity   Hormones affect only specific target tissues with specific receptors Receptors are dynamic and constantly synthesized and broken down   Down-regulation Up-regulation 27 Effects of [Hormone] on Tissue Response   Priming effect (upregulation):  Increase number of receptors formed on target cells in response to particular hormone.  Greater response by the target cell. Desensitization (downregulation):  Prolonged exposure to high [polypeptide hormone].  Subsequent exposure to the same [hormone] produces less response.  Decrease in number of receptors on target cells. ▪ Insulin in adipose cells.  Pulsatile secretion may prevent downregulation. 28 Effects of [Hormone] on Tissue Response     [Hormone] in blood reflects the rate of secretion. Half-life:  Time required for the blood [hormone] to be reduced to ½ reference level.  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. 29 30 31 Signals get translated into cellular responses or changes in gene expression Mechanisms of Hormone Action   Hormones of same chemical class have similar mechanisms of action.  Similarities include:  Location of cellular receptor proteins depends on the chemical nature of the hormone.  Events that occur in the target cells. To respond to a hormone:  Target cell must have specific receptors for that hormone (specificity).  Hormones exhibit:  Affinity (bind to receptors with high bond strength).  Saturation (low capacity of receptors). 33 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 34 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 35 ligand A small molecule that binds specifically to a larger one; for example, a hormone is the ligand for its specific protein receptor. 36  Membrane receptors membrane Glycoprotein  Intracellular receptors Cytosol or nuclei DNA binding protein 37 1. membrane receptors (1) Ligand-gate ion channels type (cyclic receptor) ligand→receptor→ion channel open or close 38 39 40 41 (2) G Protein-Coupled Receptors 1) 7-helices transmembrane receptor 42 Oligosaccharide unit Cytosolic side 43 2) G protein (Guanylate binding protein) G protein refers to any protein which binds to GDP or GTP and act as signal transduction.  G proteins consist of three different subunits (, , subunit) bound to GDP when exchanged to GTP activate -subunit  -subunit carries GTPase activity, binding and hydrolysis of GTP.  44 45 46 Neurotransmitter “Second Messenger” System 47 48 cAMP ATP 49 - Pathway of G protein linked receptor H R G protein Es secondary messeger Protein kinase Phophorylation of Es or functional protein Biological effect 50 Properties of binding of H and R  highly specificity  highly affinity  saturation  reversible binding  special function model 51 Receptor Types  Channel-linked receptors   Enzyme-linked receptors    Protein kinases  phosphorylation Neurotrophins G-protein-coupled receptors   Ionotropic Metabotropic Intracellular receptors  Activation by cell-permeant signals ~ 52 53 Receptors determine response No receptor - no response G Protein Signal Cascade The signal is usually passed from a 7-helix receptor to an intracellular G-protein.  Seven-helix receptors are thus called GPCR, or G-Protein-Coupled Receptors.  Approx. 800 different GPCRs are encoded in the human genome. G Protein Signal Cascade G-protein-Coupled Receptors may dimerize or form oligomeric complexes within the membrane. Ligand binding may promote oligomerization, which may in turn affect activity of the receptor. Various GPCR-interacting proteins (GIPs) modulate receptor function. Effects of GIPs may include:  altered ligand affinity  receptor dimerization or oligomerization  control of receptor localization, including transfer to or removal from the plasma membrane  promoting close association with other signal proteins G Protein Signal Cascade  G-proteins are heterotrimeric, with 3 subunits , , .  A G-protein that activates cyclic-AMP formation within a cell is called a stimulatory G-protein, designated Gs with alpha subunit Gs.  Gs is activated, e.g., by receptors for the hormones epinephrine and glucagon. The -adrenergic receptor is the GPCR for epinephrine. G Protein Signal Cascade hormone signal • The  subunit of a Gprotein (G) binds GTP, and can hydrolyze it to GDP + Pi. outside GPCR plasma membrane   AC GDP GTP GTP GDP cytosol ATP cAMP + PP i •  &  subunits have covalently attached lipid anchors that bind a G-protein to the plasma membrane cytosolic surface. • Adenylate Cyclase (AC) is a transmembrane protein, with cytosolic domains forming the catalytic site. Adenylate Cyclase Adenylate Cyclase (Adenylyl Cyclase) catalyzes: ATP à cAMP + PPi N N Binding of certain hormones (e.g., epinephrine) to the outer surface of a cell activates Adenylate Cyclase to form cAMP within the cell. N N H2 5' C 4' O Cyclic AMP is thus considered to be a second messenger. NH2 cAMP O O H H 3' O P O- H 1' 2' H OH G Protein Signal Cascade The sequence of events by hormone signal which a hormone activates cAMP signaling: 1. Initially Gα has bound GDP, and α, β, & γ subunits are complexed together. Gβ, γ, the complex of β, & γ subunits, inhibits Gα. outside GPCR plasma membrane   AC GDP GTP GTP GDP cytosol ATP cAMP + PP i G Protein Signal Cascade 2. Hormone binding, usually to an extracellular domain of a 7-helix receptor (GPCR), causes a conformational change in the receptor that is transmitted to a G-protein on the cytosolic side of the membrane. The nucleotide-binding site on G α becomes more accessible to the cytosol, where [GTP] > [GDP]. Gα releases GDP & binds GTP (GDP-GTP exchange). hormone signal outside GPCR plasma membrane   AC GDP GTP GTP GDP cytosol ATP cAMP + PP i G Protein Signal Cascade 3. Substitution of GTP for GDP causes another conformational change in hormone signal Gα. GPCR Gα -GTP dissociates from the inhibitory β, γ complex & can now bind to and activate Adenylate Cyclase. outside plasma membrane   AC GDP GTP GTP GDP cytosol ATP cAMP + PP i G Protein Signal Cascade 4. Adenylate Cyclase, activated by the stimulatory Gα-GTP, catalyzes synthesis of cAMP. 5. Protein Kinase A (cAMP Dependent Protein Kinase) catalyzes transfer of phosphate from ATP to serine or threonine residues of various cellular proteins, altering their activity. hormone signal outside GPCR plasma membrane   AC GDP GTP GTP GDP cytosol ATP cAMP + PP i Turn off of the signal: 1. Gα hydrolyzes GTP to GDP + Pi. (GTPase). The presence of GDP on G α causes it to rebind to the inhibitory βγ complex. Adenylate Cyclase is no longer activated. 2. Phosphodiesterases catalyze hydrolysis of cAMP  AMP. Phosphodiesterase enzymes catalyze: cAMP + H2O  AMP N N The phosphodiesterase that cleaves cAMP is activated by phosphorylation catalyzed by Protein Kinase A. N N H2 5' C 4' O Thus cAMP stimulates its own degradation, leading to rapid turnoff of a cAMP signal. NH2 cAMP O O H H 3' P O O- H 1' 2' H OH Enzyme-linked receptors: 1. Tyrosine kinase-linked receptors (TKRs). A. Overview of TKRs: 1. Cell surface receptors that are directly linked to intracellular enzymes (kinases). 2. Includes receptors for most growth factors (NGF, EGF. PDGF), insulin, and Src. 3. Common structure: N terminal extracellular ligand-binding domain, single TM domain, cytosolic Cterminal domain with tyrosine kinase activity. 4. Can be single polypeptide or dimer. 66 Examples of tyrosine kinase-linked receptors (TKRs): 67 C. Enzyme-linked receptors, cont.: 1. Tyrosine kinase-linked receptors (TKRs) B. Mechanism of activation of TKRs: i. ligand binding induces receptor dimerization (receptor crosslinking). ii. dimerization leads to autophosphorylation of the receptor (cross-phosphorylation). iii. phosphorylation increases kinase activity & also creates specific new binding sites. iv. proteins that bind to these new binding sites transmit intracellular signals. 68 69 How receptor tyrosine kinases work together with monomeric GTPases: 70 C. Enzyme-linked receptors, cont.: 1. Tyrosine kinase-linked receptors (TKRs) C. Different ways that TKRs can be activated: i. Ligand dimerization ii. Monomeric ligand binds to a crosslinking protein iii. Clustered monomeric cell-surface ligand 71

Receptors Functions and Signal Transduction L1-L2

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