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LG Goal 1 - General Principles pt.1

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General principles of
endocrinology
Contact
Karron J. James, Ph.D.
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Office: GB6, Block B
Email: [email protected]
Phone 484-8900 ext 1041
Office hours: Mon – Fri 9am-10am, 3pm-4pm
on Microsoft Teams® OR by appointment
Goal 1: To understand the general principles of
endocrine physiology
Learning Objectives
a. List the principal endocrine organs and tissues.
b. Contrast the terms endocrine, paracrine, and autocrine and give an
example of each.
c. Describe the secretion, transport in the circulation, cellular mechanisms
of action, regulation of receptors and other characteristics of peptide,
steroid, and amine (tyrosine) hormones.
d. With examples, contrast the location and signalling pathways of
membrane bound and intracellular hormone receptors.
e. Compare and contrast hormone actions that are exerted through
changes in gene expression with those exerted through changes in protein
activity, such as through phosphorylation
f. For membrane bound hormone receptors, describe the process of
activation, inactivation, up-regulation, down-regulation, sensitization, and
desensitization
Readings
Molina, P.E. (2018). Endocrine Physiology (5th ed.)
McGraw-Hill Education
http://auamed.idm.oclc.org/login?url=https://access
medicine.mhmedical.com/book.aspx?bookid=2343
Chapter 1: General Principles of Endocrine Physiology
• The endocrine system: physiologic functions and
components
• Hormone chemistry and mechanisms of action (up
to and incl Fig 1-3)
• Hormone receptors and signal transduction
Objective 1a. List the principal endocrine
organs and tissues
Fig 1-1. Molina
Signalling Basics
• Cell communication: transduction of message
from one cell to (usually) another cell resulting
in altered behaviour of target cell
• Basic requirements:
– Signalling cell
– Extracellular ligand (hormone)
– Target (responding) cell
– Receptor (plasma membrane or intracellular)
Goal 1: To understand the general principles of
endocrine physiology
Learning Objectives
a. List the principal endocrine organs and tissues.
b. Contrast the terms endocrine, paracrine, and autocrine and give an
example of each.
c. Describe the secretion, transport in the circulation, cellular mechanisms
of action, regulation of receptors and other characteristics of peptide,
steroid, and amine (tyrosine) hormones.
d. With examples, contrast the location and signalling pathways of
membrane bound and intracellular hormone receptors.
e. Compare and contrast hormone actions that are exerted through
changes in gene expression with those exerted through changes in protein
activity, such as through phosphorylation
f. For membrane bound hormone receptors, describe the process of
activation, inactivation, up-regulation, down-regulation, sensitization, and
desensitization
Obj 1b: Contrast the terms endocrine,
paracrine, and autocrine and give an example
of each
• Signalling by secreted molecules
1. Endocrine: bloodstream
2. Paracrine: nearby
3. Autocrine: self
Fig 1-3. Molina
•All signalling molecules only active on target cells that express an appropriate
receptor
Goal 1: To understand the general principles of
endocrine physiology
Learning Objectives
a. List the principal endocrine organs and tissues.
b. Contrast the terms endocrine, paracrine, and autocrine and give an
example of each.
c. Describe the secretion, transport in the circulation, cellular mechanisms
of action, regulation of receptors and other characteristics of peptide,
steroid, and amine (tyrosine) hormones.
d. With examples, contrast the location and signalling pathways of
membrane bound and intracellular hormone receptors.
e. Compare and contrast hormone actions that are exerted through
changes in gene expression with those exerted through changes in protein
activity, such as through phosphorylation
f. For membrane bound hormone receptors, describe the process of
activation, inactivation, up-regulation, down-regulation, sensitization, and
desensitization
Hormones
• Regulate physiologic processes, eg.
reproduction, growth, metabolism
• Can be classified as peptide, steroid, amine
Peptide or Protein Hormones
• Inactive precursor stored in
secretory vesicles near plasma
membrane, released via
exocytotic pathway
•
Bind plasma membrane
receptors
Major classes of plasma membrane
receptors
1.
2.
3.
4.
Ligand-gated ion channels
GPCR
Enzyme-coupled
Cytokine receptors
1. Ligand-gated Ion Channel
• Ionotropic receptor
• Membrane protein
complex that includes
ligand binding sites
forms a pore
Ion
Signaling
molecule
• Example?
https://www.nature.com/scitable/topicpage/ion-channel-14047658
2. G protein-coupled receptor
• a.k.a. 7-TM domain receptor
• Relies on second messengers
to relay intracellular signals
• Binding  phosphorylation
of GDP associated with
trimeric G protein complex
Fig 1-5. Molina
Gα proteins
• Gαs
– Activates adenylyl cyclase
• Gαi
– Inhibits adenylyl cyclase
• Gαq
– Activates phospholipase C
• Gα12/13
– Activates RhoA
GPCR—Gs signalling
Fig 1-5. Molina
Fig 15-33. Alberts.
GPCR—Gi signalling
Fig 1-5. Molina
https://www.news-medical.net/whitepaper/20170525/Using-CLARIOstarc2ae-Microplate-Reader-forReal-Time-Detection-of-Gi-and-Gs-Signaling-in-Living-Cells.aspx
GPCR—Gq signalling
example,
OXYTOCIN
Fig 15-36. Alberts.
Fig 1-5. Molina
GPCR—G12/13 Signalling
• Receptor ligands: thrombin, lysophosphatidic acid,
sphingosine-1-phosphate, thromboxane A2
• Receptor activation
 activation of
Rho GEF 
activation of RhoA
• Effects in the
cytoplasm and in
nucleus
Fig 1-5. Molina
3. Enzyme-coupled Receptors
• Serine-threonine kinase
Fig. 15-65. Alberts.
• Receptor tyrosine kinase
https://www.nature.com/scitable/topicpage/rtk-14050230
RTK Signalling can occur via 3
pathways
• Signal transduction
pathways:
a. PI3-K
b. Ras/MAPK (Grb/SOS)
c. PLC
Fig 8-1. Goodman, S.R. Medical Cell Biology. 3ed. Academic Press.
a. PI3-K Pathway—insulin, IGF-1 signalling
• Ligand binding RTK~P
• Activated RTKs recruit IRS, and
phosphorylate
• formation of binding sites for
PI3-K, also phosphorylated
• PI3-K: PIP2 PIP3
• PIP3 recruits Akt (PKB),
phosphorylates it
phosphorylation cascade
downstream
• GLUT4 translocates to
membrane. Lipid, protein
synthesis, etc.
Fig 1-6
https://employees.csbsju.edu/hjakubowski/classes/ch331/signaltrans/ST_9
C9_Insulin_Sig_PI3K_Ak.html
b. RAS/MAPK Pathway
• Activated RTKs recruit intracellular
signal transducers near membrane,
Eg. Shc, IRS1. Phosphorylates
• Formation of binding sites for
Grb2. Phosphorylates
• Grb2/SOS catalyzes conversion of
Ras from inactive to active (GTPbound) form
• Ras-GTP interacts with and
stimulates downstream effectors,
leading to activation of the MAP
kinases ERK1 and 2
• ERKs enter nucleus, phosphorylate
and activate Tc factors for growth,
differentiation
Insulin
(Insulin
receptor)
c. PLC Pathway
• Activated RTKs recruit
intracellular signal
transducers near membrane
– Bind and phosphorylate
substrates w/ SH2 domains, eg.
PLCγ stimulation of
phospholipase activity
• PLC: PIP2 IP3, DAG
• IP3 Ca2+ release from ER
•
Ca2+,
DAG activate
PKC activate Tc of
genes involved in
proliferation, survival, etc.
http://publication.letstalkacademy.com/ip3-dag-pathway-of-receptor-tyrosinekinase-in-cell-signalling
Receptor Serine Threonine Kinases
• When activated, cell
surface receptors
phosphorylate S or T on
substrate proteins
• One of a group of
receptors that binds TGFβ family of signalling
molecules
• Ligand-receptor complex
binds Smad proteins
• Smads enter nucleus to
regulate transcription of
target genes
Fig. 15-65. Alberts.
4. Class I Cytokine Receptors
• No intrinsic TK activity
• Associate with ‘non-receptor
(cytosolic) tyrosine 2’—Jak2
• Jak/STAT pathway
Fig 1-6
Steroid Hormones
• Include adrenal (eg. cortisol),
sex hormones (testosterone,
estradiol, progesterone)
– Adrenal cortex, gonads,
placenta
• Bind receptor in the
cytoplasm
• Ligand binding  binding
of DNA regulatory sequence
(HRE) by complex 
regulation of transcription
studyblue.com
Steroid hormones
• Derived from cholesterol
•
Synthesized and quickly
released  bloodstream,
bound by carrier proteins 
hormone, only, taken up by
target cell
• Vitamin D3
Retinoic acid
• Not a steroid hormone
• Retinoic acid—synthesised from retinol, not
cholesterol
• Tc factor, important for patterning during
embryogenesis
– Receptor located in nucleus
Amine Hormones
Eg. Thyroid hormones,
epinephrine*, norepinephrine*
Goal 1: To understand the general principles of
endocrine physiology
Learning Objectives
a. List the principal endocrine organs and tissues.
b. Contrast the terms endocrine, paracrine, and autocrine and give an
example of each.
c. Describe the secretion, transport in the circulation, cellular mechanisms
of action, regulation of receptors and other characteristics of peptide,
steroid, and amine (tyrosine) hormones.
d. With examples, contrast the location and signalling pathways of
membrane bound and intracellular hormone receptors.
e. Compare and contrast hormone actions that are exerted through
changes in gene expression with those exerted through changes in protein
activity, such as through phosphorylation
f. For membrane bound hormone receptors, describe the process of
activation, inactivation, up-regulation, down-regulation, sensitization, and
desensitization
Regulation mechanisms:
See Fig 15-25. Alberts.
Response to ligand-binding is
regulated
• Receptors may be up-regulated
– May be response to reduced level of ligand
– Increase transcription, translation
• Decrease degradation of receptors
• Activation of receptor
• Receptors may be down-regulated
– Reduce transcription, translation
• Increase degradation of receptors
Target cell can be sensitized or
de-sensitized
• Desensitization (adaptation) can
occur after repeated or chronic
exposure of receptor to hormone
• Reduced response to future
stimulation by same ligand or
same concentration of ligand
– Over time, no response to same
ligand concentration
– Need greater ligand concentration
to produce response
Fig 15-48. Alberts.
• Can occur by receptor
sequestration, receptor downregulation, receptor inactivation
(eg. by phosphorylation)
Goal 1: To understand the general principles of
endocrine physiology
Learning Objectives
a. List the principal endocrine organs and tissues.
b. Contrast the terms endocrine, paracrine, and autocrine and give an
example of each.
c. Describe the secretion, transport in the circulation, cellular mechanisms
of action, regulation of receptors and other characteristics of peptide,
steroid, and amine (tyrosine) hormones.
d. With examples, contrast the location and signalling pathways of
membrane bound and intracellular hormone receptors.
e. Compare and contrast hormone actions that are exerted through
changes in gene expression with those exerted through changes in protein
activity, such as through phosphorylation
f. For membrane bound hormone receptors, describe the process of
activation, inactivation, up-regulation, down-regulation, sensitization, and
desensitization
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