Last edited: 9/28/2021

1. RECEPTOR PATHWAYS
Endocrinology | Receptor Pathways Medical Editor: Ilia-Presiyan Georgiev

OUTLINE (2) The G protein is normally bound to GDP

Binding of a peptide hormone (e.g., epinephrine or
I) HORMONES oxytocin) changes the overall three-dimensional
II) G PROTEIN-COUPLED RECEPTORS (GPCR)
structure of the inside portion of the receptor
III) STEROID HORMONR RECEPTORS
o The receptor activates the G protein by removing the
IV) INHIBITION
V) APPENDIX GDP and adding on GTP
VI) REVIEW QUESTIONS The activated G protein can move along the membrane
VII) REFRENCES o Because it is a peripheral membrane protein
‘Off’ state – inactive receptor
I) HORMONES o The G protein is bound to GDP
(1) Peptide hormones ‘On’ state – active receptor
o GDP is removed and GTP is added
Oxytocin, insulin, glucagon, FSH, LH, GH, PTH, ADH etc.
Water soluble
o Have a hydrophilic amino acid
o Do not precipitate
Do not pass freely through the cell membrane
(phospholipid bilayer)
o Relatively big size
o Charged
o Water soluble proteins can’t penetrate phospholipid
barrier
Require a receptor on the cell membrane
o Utilizes the 2nd Messenger Systems (Gs, Gq, Gi)
(2) Steroid hormones
Testosterone, estrogen, progesterone, aldosterone,
cortisol, gonadocorticoids, etc. Figure 2 G protein-coupled receptor’s ‘on’ and ‘off’ states.
Lipid soluble
o Derived from cholesterol
(B) GS PROTEIN-COUPLED RECEPTORS
Pass through the phospholipid barrier
Bind to receptors inside the cell (1) G stimulatory protein.
The activated Gs protein goes to an effector enzyme on
the cell membrane – Adenylate cyclase
o The effector enzyme has a specific point of
attachment for the Gs protein
The effector enzyme becomes very active
(2) Adenylate cyclase
has a specific enzyme – GTPase
o GTPase cuts the GTP and turns it into GDP (removes
a phosphate)
 G protein is turned off
o Energy is produced and used to convert ATP to
cAMP
 cAMP activates protein kinase A (pkA)

A kinase, by definition, is an enzyme that phosphorylates

Figure 1 Peptide (blue) and steroid (red) hormones interacting
with a cell.

II) G PROTEIN-COUPLED RECEPTORS (GPCR)

(1) Receptor structure

Receptor with seven transmembrane helices
o Structure protein passes through the membrane 7
times
o A.k.a seven pass transmembrane receptors or
‘serpentine’ receptors
Binding sites for ligands are found in extracellular Figure 3 Gs coupled-protein receptor pathway.
regions or between helices.
o Has an intracellular binding site for the G protein

Receptor Pathways ENDOCRINE PHYSIOLOGY: Note #1. 1 of 4

(3) The activated pkA
can phosphorylate multiple proteins which leads to
different effects:
o Regulation of membrane permeability for different
ions
 Phosphorylation of channel proteins on the cell
membrane
o Regulation of metabolic pathways (glycolysis)
 Phosphorylation of enzymes
o Increased production of new proteins (transcription)
 Phosphorylation of transcription factor
o Increased cell proliferation and DNA replication,
etc.

Figure 5 Gq protein-coupled receptor's pathway (Oxytocin).

III) STEROID HORMONR RECEPTORS

Can be intra cytosolic or intranuclear
Normally are bound to heat shock protein (HSP)
o ‘Off’ state
When a steroid hormone (testosterone) goes through the
cell membrane and binds to the receptor it displaces the
HSP and activates the receptor
o ‘On’ state
The activated receptor binds to a specific gene sequence
Figure 4 Effects of protein kinase A.
– hormone response element (HRE)
A plethora of effects is triggered:
(C) GQ PROTEIN-COUPLED RECEPTORS o DNA replication
 Stimulates cell proliferation (mitosis)
(1) The activated Gq protein o Transcription followed by translation
goes to an effector enzyme on the cell membrane –  Stimulates the synthesis of proteins that:
Phospholipase C • Control metabolism
o The effector enzyme has a specific point of • Control ion permeability
attachment for the Gq protein • Control protein synthesis
o The effector enzyme becomes very active • Control cell growth

(2) Phospholipase C
has a specific enzyme – GTPase
o GTPase cuts the GTP and turns it into GDP
 G protein is turned off
o Energy is produced and used to cut a specific
molecule that is found in the membrane -
phosphatidylinositol biphosphate (PIP2) into
diacylglycerol (DAG) and inositol trisphosphate
(IP3)
 DAG activates a specific enzyme – protein
kinase C (pkC)
(3) pkC has the same function as pkA
Phosphorylation of different proteins
o Leads to activation or deactivation
IP3 affects the smooth endoplasmic reticulum in most
cells or the sarcoplasmic reticulum in muscle cells.
o The reticulum has specific receptors for IP3
IP3 binds to the receptor to open a specific channel Figure 6 Steroid hormone receptor pathway.
o Calcium (Ca++) leaves the reticulum and goes in the
cytoplasm.
IV) INHIBITION
(4) Calcium (Ca++)
binds to Calmodulin which then activate different types The enzyme phosphodiesterase (PDE) breaks down
of kinases cAMP or Phospholipase C to prevent these pathways
The activated kinases phosphorylate different proteins from continuously occurring.
o e.g., myosin to initiate contractions

This is the mechanism oxytocin uses to increase the calcium

levels inside the cell in order to cause contractions
Figure 7 Effects of phosphodiesterase.

2 of 4 ENDOCRINE PHYSIOLOGY: Note #1. Receptor Pathways

 V) APPENDIX

Locations of the “Off” “On”

Examples Solubility Effectors
receptors state state
Peptide Oxytocin, insulin, glucagon, FSH, LH, Water On the cell
GDP GTP Kinases
hormones GH, PTH, ADH soluble membrane
Testosterone, estrogen,
Steroid Lipid In the cytosol or in Steroid
progesterone, aldosterone, cortisol, HSP HRE
hormones soluble the nucleus hormone
gonadocorticoids

VI) REVIEW QUESTIONS

Which hormone is peptide in nature?
a. Estrogen What is hormone response element?
b. Glucagon a. Effector enzyme
c. Aldosterone b. Gene sequence
d. Cortisol c. Peptide hormone
d. Channel transporter
Which hormone is steroid in nature?
a. Oxytocin Which enzyme activates the GPCR?
b. Growth hormone a. Protein Kinase C
c. Insulin b. Adenylate Cyclase
d. Testosterone c. Phosphodiesterase
d. GTPase
What is a typical property of peptide hormones? CHECK YOUR ANSWERS
a. Can bind to intranuclear receptors
b. Water soluble VII) REFRENCES
c. Can freely pass through a phospholipid barrier
d. Derived from cholesterol ● Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for
the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017
What is a typical property of steroid hormones? ● Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ:
Pearson; 2020.
a. Lipid soluble ● Boron WF, Boulpaep EL. Medical Physiology.; 2017.
b. Large size ● Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL,
c. Have a hydrophilic amino acid in its structure. Loscalzo J. Harrison's Principles of Internal Medicine, Twentieth
Edition (Vol.1 & Vol.2). McGraw-Hill Education / Medical; 2018
d. Can bind to membrane receptors ● Hall JE, Hall ME. Guyton and Hall Textbook of Medical
Physiology. Philadelphia, PA: Elsevier; 2021.
Which molecule is related to the ‘on’ state of peptide
hormones?
a. ATP
b. HSP
c. GDP
d. GTP

Which molecule is related to the ‘off’ state of steroid

hormones?
a. cAMP
b. GDP
c. HRE
d. HSP

Which enzymes activated in the GsPCR pathway?

a. Protein Kinase C
b. Adenylate Cyclase
c. Phosphodiesterase
d. Phospholipase C

Which enzymes activated in the GqPCR pathway?

a. Phosphodiesterase
b. Adenylate Cyclase
c. Protein Kinase A
d. Phospholipase C

Receptor Pathways ENDOCRINE PHYSIOLOGY: Note #1. 3 of 4

4 of 4 ENDOCRINE PHYSIOLOGY: Note #1. Receptor Pathways