SF3 Guanylate Cyclase Flashcards
What receptors are linked to guanylate cyclase?
Atrial natriuretic peptide receptor
Guanylin receptor family
Photoreceptor dark cycle
What is the purpose of guanylate cyclase on receptors?
It is to phosphorylate the GTP into cyclic GMP so that it can act as a 2nd messenger
Where is the atrial natriuretic peptide receptor found?
Within the cell membrane of cardiac cells
Where is the guanylate cyclase found?
It can be found within the ANP receptor but also cytosolically.
Both will activate cyclic GMP
What is the importance of guanylate cyclase domains also being found in the cytosol?
It means that small lipophilic molecules like nitric oxide can cross the membrane into the cell and activate the conversion to cyclic GMP
How does the activation of guanylate cyclase impact the cardiac system?
The cyclic GMP will go onto to phosphorylate protein kinase G which will result in muscle relaxation and vasodilation
Which other structures belong to the family of natriuretic peptides?
ANP - mainly in the atria
BNP - found in the brain but thought to be mostly produced by the ventricles of the heart
CNP - both in the central nervous system and the endothelium
DNP - only in reptiles
What is responsible for degrading natriuretic peptides?
Neutral endopeptidase (NEP)
Nephrilysin
How many types of natriuretic peptide receptors are there?
3
NPR A
NPR B
NPR C
What is different about NPR C?
It is dimerised even in the absence of an agonist
It is referred to as a clearance receptor
There is no catalytic activity or guanylate cyclase domain associated with it
Which atrial natriuretic peptides can bind to NPR A?
ANP
BNP
Which atrial natriuretic peptides can bind to NPR C?
All three
ANP
BNP
CNP
Which natriuretic peptides can bind to the NPR B?
CNP
What does natriuretic peptide receptor A do?
Regulates blood volume and pressure
Associated with cardiac remodelling
What does natriuretic peptide receptor B do?
Promotes growth of long bones
What does natriuretic peptide receptor C do?
It’s a clearance receptor and lack guanylate cyclase
Involved in trafficking peptides and internalising them so that they may be recycled (lysosomes)
Is NPR C the only one that internalise the various peptides?
NPR A and NPR B may be able to internalise peptides but this is thought to be associated with desensitisation or signal transduction
How many types of natriuretic peptide receptors are there thought to be be?
In humans there are five confirmed NPRs
The two associated with dark photoreceptor cycles are thought to be cytosolic as there’s no extracellular ligand know for them
Describe the guanylin receptor family
A novel endocrine axis linking the digestive system and kidney in the regulation of salt homeostasis
What ligands are associated with the guanylin receptor family?
Guanylin
Uroguanylin
Lymphoguanylin
Bacterial enterotoxins mimic the other ligands to use these receptors
What is the physiological role of Guanylin receptors?
Receptors found in the intestinal mucosa will increase trans epithelial secretion of Cl-, HCO3-, H2O into the lumen
Receptors in the kidney help monitor sodium and potassium loss
Give an example of how Guanylin receptors can be targeted by pharmaceuticals
Laxatives and anti diarrhoeal agents
Diuretics
Where does the nitric oxide bind to on cytosolic guanylate cyclase?
The haem (Fe) group
What conditions can be treated by prolonging the interaction of nitric oxide with the guanylate cyclase?
Pulmonary arterial hypertension
Acute heart failure
Give an example of a drug that delays the dissociation of nitric oxide from the haem group
Riociguat
Nitric oxide sensitising drug
What is the structure of the cytosolic guanylate cyclase?
2 isoforms of each subunit
Homo and hetero dimers
Haem binding domain
Dimerisation domain
Catalytic domain
Since there are two Isoforms of cytosolic guanylate cyclase what does this mean?
There can be homo and heterodimers
Is nitric oxide the only activator of cytosolic guanylate cyclase?
No there are nitric oxide independant activators such as cinaciguat
How is cyclic GMP cleared from inside the cell before returning to resting levels?
Primarily by bind to the catalytic site of phosphodiesterases and being broken down to 5-GMP which cannot activate any of the internal structures
May also be removed from the cell all together
