l3 325 2012 w_ notes

7/30/2019 L3 325 2012 w_ notes

http://slidepdf.com/reader/full/l3-325-2012-w-notes 1/55

CSB 325 Lecture 3: Study of Endocrinology

Introduction to Endocrinology

1. Philosophical Aspects2. Definitions of Hormones

3. Hormone Classes and Structures

4. Receptor Mechanisms

7/30/2019 L3 325 2012 w_ notes



1. Philosophical Aspects

Signalling molecules

Homeostatic control

Communication

Information transfer

7/30/2019 L3 325 2012 w_ notes




Traditionally, after the work of Claude Bernard in the 1800’s endocrinology was

defined as secretions from the ductless glands.

The physiological goal of these secretions were to maintain a physiological balance

or homeostasis within an organism

This led to the isolation of hormones such as insulin and secretin in the early 1900s

In the first half of the 20th century, description of the neurosecretory cell andneuroendocrine circuits led to the isolation of a constellation of bioactive

molecules.

Finding these active molecules in all tissues led to a refinement of endocrinology

as the study of signalling molecules.

7/30/2019 L3 325 2012 w_ notes




Because such molecules were produced by one cell type to signal to another cell

type, the concept of cell-to-cell and tissue-to-tissue communication became

entrenched into the study of endocrinology

With the advent of information theory, in the last 30 years, this concept was

applied to endocrinology. Thus endocrinology and signalling molecules became

associated with the transfer of information from one tissue or cell to another tissue

or cell.

In the modern sense, the study of endocrinology involves all elements:

homeostasis, cell signalling, communication and information transfer

7/30/2019 L3 325 2012 w_ notes


Chemical signal – Information transfer

Signalgenerator

Signalreceiver

Output


Input

7/30/2019 L3 325 2012 w_ notes



2. Definitions of Hormones

In the strict sense, a hormone is a signalling molecule that is released by a tissue

into the blood stream and interacts with another tissue.

In this respect, a hormone is therefore one type of signalling molecule

However, now a hormone is frequently considered to be synonymous with

signalling molecules.

Thus a traditional ‘hormone’ is now considered an ‘endocrine hormone’

7/30/2019 L3 325 2012 w_ notes


CSB 325 Lecture 3

Endocrine Processes and types of cell

Signalling mechanisms:

Autocrine

ParacrineJuxtacrine

Intracrine

Endocrine

Neuroendocrine

Exocrine

7/30/2019 L3 325 2012 w_ notes


Signaling types


7/30/2019 L3 325 2012 w_ notes


Autocrine and Paracrine Signalling Networks

Autocr ine Signal ing:

A chemical releasedfrom a cell binds toa receptor on the same

cell or an identical cellto modulate the activityof that cell.

Paracrine Signaling:

A chemical releasedfrom a cell binds toa receptor on a

different type of cell

Autocrine and paracrine systemsdo not utilize a vascular system


7/30/2019 L3 325 2012 w_ notes


Juxtacrine Signalling Systems are stationary

signalling systems between two cells or the celland the extracellular matrix

Membrane-boundreceptor

Components of theExtracellular matrix


7/30/2019 L3 325 2012 w_ notes


Juxtacrine Signalling Systems

Membrane-boundligand





7/30/2019 L3 325 2012 w_ notes


Juxtacrine Signalling Systems

Membrane-boundligand




Signal transduction


7/30/2019 L3 325 2012 w_ notes


Notch as an example of J uxtacrine signalling

The receptor, notch, bindsto its ligand, delta


7/30/2019 L3 325 2012 w_ notes


Intracrine Signalling:

Molecules that transfer

information or signalbetween organelles in

a cell.cell

organelle


7/30/2019 L3 325 2012 w_ notes


Nervous-Endocrine Interactions:Neuroendocrine signalling

Nervouscomponent

Neuroendocrine

componentReleasing Factors

NeurohormonesEndocrinecomponent

SensoryInformation

Tissues

Neurotransmitters

Neuromodulators

Neurotransmitters

Neuromodulators

Hormones


7/30/2019 L3 325 2012 w_ notes


Chemical Espionage

Sex attractants

Reproductive regulators


Exocrine signalling involves the release

of signalling molecules from one organism

to another.

Such signalling agents are referred to

as pheromones

7/30/2019 L3 325 2012 w_ notes


Semiochemicals

Pheromones

Between species Within species

Alleochemicals

Kairomones Allomones Synomones


Pheromones are part of a larger group of exocrine signals called Semiochemicals

7/30/2019 L3 325 2012 w_ notes



Endocrine and Exocrine Signal Transmission

7/30/2019 L3 325 2012 w_ notes


A few words about Endocrine systems…

Any cell that evolved the capability for robust paracrine secretion hadthe potential to become and endocrine cell.

These cells were present in all the basic tissue types of the earliestMetazoans, therefore, all tissues had the capability of becomingEndocrine organs.

In fact, this is the case today: all tissues and organs have a variety of Substances that are secreted into the blood stream.

Therefore, all organs, by definition, may be considered endocrine organs.


7/30/2019 L3 325 2012 w_ notes


Basic signalling systems:

Growth and Differentiationfeeding,growthmaturation

cell cycledifferentiationcell death

Sensory systemslocomotion

toward food sourceaway from danger

chemical (olfactory input)visual (input)geotaxismechanical


7/30/2019 L3 325 2012 w_ notes



3. Hormone Classes and Structures

Hormone and chemical signals can include several different types of structures

7/30/2019 L3 325 2012 w_ notes


Types of Signalling Molecules

Amino acids

among first amino acids synthesized

acid/base ability

form elongated chains

Peptides and Proteins

structural and signalling abilityseveral types of structural organization

can carry and transmit information

Lipids: fatty acids and steroids

pass through membrane

early prebiotic synthesis

Gases and ions

present in prebiotic Earth

Nucleic acids

common as signal molecules but

evolutionary origins are not clear


7/30/2019 L3 325 2012 w_ notes


Modified Amino Acids

Amino acids can be modified into additional signallingMolecules.

Here, the enzymes that regulate the biosynthetic pathwayAre encoded by the genes.

The expression of these genes is cell and tissue dependent


7/30/2019 L3 325 2012 w_ notes


Glycine, Glutamate and GABA

Glycine, glutamate and GABAare simple chemical signalsthat have their origin inthe prebiotic earth


7/30/2019 L3 325 2012 w_ notes


Modified Amino Acids: Catecholamines


7/30/2019 L3 325 2012 w_ notes


Monoamines


7/30/2019 L3 325 2012 w_ notes


Thyroid Hormones


7/30/2019 L3 325 2012 w_ notes


Acetylcholine Synthesis

Although not a modified amino acid per se, it incorporatesBoth acid and amino groups


Acetylcholine is an ester of acetic acid and

choline, with the chemical formula

CH3COOCH2CH2N+(CH3)3

Its structural chemical name is 2-(acetyloxy)-

N,N,N-trimethylethanaminium

http://en.wikipedia.org/wiki/Ester

http://en.wikipedia.org/wiki/Acetic_acid

http://en.wikipedia.org/wiki/Choline

http://en.wikipedia.org/wiki/Acetyl

http://en.wikipedia.org/wiki/Oxygen

http://en.wikipedia.org/wiki/Nitrogen

http://en.wikipedia.org/wiki/3_(number)

http://en.wikipedia.org/wiki/Methyl

http://en.wikipedia.org/wiki/Ethane

http://en.wikipedia.org/wiki/Amine

http://en.wikipedia.org/wiki/Amine

http://en.wikipedia.org/wiki/Ethane

http://en.wikipedia.org/wiki/Methyl

http://en.wikipedia.org/wiki/3_(number)

http://en.wikipedia.org/wiki/Nitrogen

http://en.wikipedia.org/wiki/Oxygen

http://en.wikipedia.org/wiki/Acetyl

http://en.wikipedia.org/wiki/Choline

http://en.wikipedia.org/wiki/Acetic_acid

http://en.wikipedia.org/wiki/Ester

7/30/2019 L3 325 2012 w_ notes


Peptide Hormones

A fusion of amino acids incorporating thepeptide bond


7/30/2019 L3 325 2012 w_ notes


Peptide Hormones possessinformation at all levelsof organization


7/30/2019 L3 325 2012 w_ notes



Examples of Peptide hormones:

Adrenocorticotropic hormone (ACTH)

Bradykinin

Corticotropin-releasing factor (CRF)

Endorphins

Fibroblast growth factorGrowth Hormone

Insulin

Kisspeptin

Luteinizing hormone (LH)

Neuropeptide Y

ProlactinRelaxin

Secretin

Tachykinin

Urotensin-I

Vasopressin

7/30/2019 L3 325 2012 w_ notes


Figure 4-9 Arachidonic acid metabolites


Fatty acid based hormones includeA class of hormones called

Eiconsanoids and are synthesized

From arachidonic acid

7/30/2019 L3 325 2012 w_ notes


Steroids: Synthesizedin endoplasmic reticulumor mitochondria

Easily pass through

membranes

Structure of Steroid Hormones


7/30/2019 L3 325 2012 w_ notes


Cyclic nucleotides as chemical signals


7/30/2019 L3 325 2012 w_ notes



4. Receptor Mechanisms

A hormone or signalling molecule is only effective if it

binds to a receptor on the target cell.

There are several different receptor mechanisms that lead to

a variety of different signal transduction events.

7/30/2019 L3 325 2012 w_ notes


Hormone Receptor Systems

Receptor Types:

Membrane Associated:

1. G-Protein Coupled Receptors

2. Ion Channels

3. Kinases

Nucleus Associated:

1. Transcription Factors


7/30/2019 L3 325 2012 w_ notes



7/30/2019 L3 325 2012 w_ notes


G-Protein Coupled Receptors

Largest class of receptors in an organism

includes olfactory, gustatory, photo receptorsas well as hormone receptors

Examples: Corticotropin-Releasing Factor FamilyNeuropeptide Y Family

Gonadotropin Releasing Hormone FamilyVasoactive Intestinal Peptide FamilyVasopressin FamilyCatecholamines

Serotonin/melatonin


7/30/2019 L3 325 2012 w_ notes


Model of a peptide ligand binding

to a G-protein coupled receptor


7/30/2019 L3 325 2012 w_ notes


7/30/2019 L3 325 2012 w_ notes


G protein coupled receptors (GPCR) have a central common core made of seventransmembrane helices (TM-I to -VII) connected by three intracellular (i1, i2, i3) and threeextracellular (e1, e2, e3) loops. Diverse messages activate the receptor at the N-terminaland the e1 loops. i2 and i3 loops are the two main loops engaged in G protein recognitionand activation. (from Bockaert and Pin, 1999).


7/30/2019 L3 325 2012 w_ notes


Receptor Kinases: Second largest Receptor family

Examples: InsulinGrowth factors

Transforming growth factorEpidermal growth factor

Cytokines Tumor necrosis factor

interleukin-1ProlactinGrowth Hormone


7/30/2019 L3 325 2012 w_ notes


Receptor tyrosine kinase Systems

Examples of hormones binding to this type of receptor:prolactin, growth hormone, leptin


7/30/2019 L3 325 2012 w_ notes


Serine/Threonine Kinase SystemsligandType I receptor

Type II receptor

Lipid bilayer

Examples of ligands: activin, transforming growth factor, inhibin


7/30/2019 L3 325 2012 w_ notes


Transforming Growth Factor Receptor Pathway


7/30/2019 L3 325 2012 w_ notes


Ligand-gated channels may represent the earliest type of hormone

receptors. At present four such receptors are known.

These include: GABA receptors, responsive to the transmitter, GABA,

Glutamate receptors, NMDA, AMPA and kainate

bind glutamate and glycine.

It is of interest that channel receptors being predicted to be one of the

oldest classes of receptors are dedicated to glutamate, GABA and

glycine.

As we saw in an earlier section, glutamate and glycine are amino acids

that are not only easily synthesized by prebiotic condit ions, but have

also been found in meteorites suggesting that these amino acids

were present at the beginning of the early development of life.

Ligand-gated channels


7/30/2019 L3 325 2012 w_ notes


GABA signals both through ionotropic receptors (GABA A,

GABAC) which induce fast synaptic inhibitory responses,

and metabotropic receptors (GABAB) which play a role in

the reduction of presynaptic transmitter release and post

synaptic inhibitory potentials. The GABA metabotropic receptors are G-protein coupled

receptors and are therefore not channel receptors The ionotropic GABA receptors are a Cl ion channel andhave an inhibitory action on the plasma membrane by

contr ibuting to its level of hyperpolarization.

GABA Receptors


7/30/2019 L3 325 2012 w_ notes


GABA A receptor

Cl-


7/30/2019 L3 325 2012 w_ notes


Glutamate Receptors

(Ion Channels) The three known types of glutamate channel receptors are named

after the ligand that was initially used to identify them. The

receptors all have an excitory action on the membrane acting to

depolarize the membrane. NMDA receptor: (N-methyl D-aspartate) plays a role in in learning

and long term potentiation. The channel allows Na+, K+, Cl- and

Ca2+ ions to pass readily through. The NMDA receptor also has a

high affinity binding site for glycine.

AMPA (α amino –3- hydroxy-5 methyl 4 isoxazoleproprionate, andkainate receptors: possess smaller ion channels allow ing Na+, K+

and Cl- but not Ca2+. The AMPA and kainate receptors have been

impl icated in the mediation of spinal cord reflexes and cortical

evoked potentials.

Glutamate wi ll also signal through a metabotropic GPCR


7/30/2019 L3 325 2012 w_ notes


Hormone

Receptor Secondary Signalling Cascade

Single Hormone/

Single Receptor

Two Paralogous Hormones/

Two Paralogous Receptors

1 response4 responses


7/30/2019 L3 325 2012 w_ notes


A B

DC

Heterodimer Homodimer

Mechanisms of Ligand Specificity

Different LigandDifferent Receptor

Different LigandSame Receptor

Different LigandReceptor dimerization Different Ligands

Receptor modifiers


d f d l

7/30/2019 L3 325 2012 w_ notes


Nuclear Receptors: Transcription Factors

Nuclear receptors are a large superfamily of related hormone-

activated transcription factors that bind structurally diverse ligands

such as retinoic acid, steroids, eicosanoids and thyroid hormones.

An additional class of these proteins are described as orphan

nuclear receptors as ligands have not been identified for them.Unlike the protein kinase or GPCRs, these proteins are typically

found in the cytosol or nucleus of cells. Lipid-soluble molecules

diffuse through the plasma and nuclear membranes bind and

regulate specific transcription factors belonging to this group of

receptors.

Peroxisome proliferatory activated receptors (PPAR) belong to the

nuclear hormone receptor superfamily. Like thyroid hormone

receptors, PPARs perform their transcriptional function as

heterodimers with retinoid X receptors Three different variants of

PPARs have been identified in amphibians, rodents and human--

PPAR alpha beta and gamma .


d f d i l

7/30/2019 L3 325 2012 w_ notes


Molecular Mechanism for Steroid Receptors


CS 32 3 S d f d i l

7/30/2019 L3 325 2012 w_ notes


Nuclear receptors:Classes and General Structure

Class I primarily cytoplasmic – GR

Class II capable of nuclear translocation independently of ligand –ER, PR

Class III Located in the nucleus, bound to DNA and in the absenceof ligand is a repressor - TR

NLS Ligand bindingDNA binding


CSB 325 L 2 S d f E d i l

7/30/2019 L3 325 2012 w_ notes


Any Questions???


l3 325 2012 w_ notes

Documents