CaSR in endothelium mediated relaxation Flashcards
The CaSR belongs to what family of the GPCR family?
It has a venus flytrap binding domain to allow ligands bind to the amino acid ligand binding pocket
It is a promiscuous receptor activated by type 1 and type 2 allosteric modulators. It is a low-affinity receptor, with an EC50 at 3mm and until 1997 is was though to be in the parathyroid gland only
What is the EC50 of CASR
3mm allowing it to respond to minimal changes in calcium levels.
How does endothelium mediate vasorelaxation
K+ Channel hyperpolarisation
Weston et al 2005
Potassium channel hyperpolarisation
Weston et al 2005
Calcimimetic induced vasorelaxation in the presence of intact endothelium of rat mesenteric artery
This relaxation inhibited by mechanical destruction of the endothelium
To confirm, calhex (inhibitor) reduced these endothelial relaxations and so did the inhibition of K+ channels by TRAM39.
Thus endothelium mediates relaxation in the presence of calcium by K+ channel activation causing K+ efflux, and this is linked to Na+/K+ as this is inhibited by ouabin
Zhang et al 2006
Via NO
In human aortic endothelial cells CaR expression confirmed by western blot and RT PCR
Using spermine to activate, there was increase in calcium as well as an increase in NO
This was inhibited by CaSR siRNA
Greenberg et al 2016
Pre-contracted rabbit mesenteric arteries with methoxamine
Stimulation of CaSR with local calcium current increasing from 1 mM to 6 mM induced concentration-dependent relaxations with 6 mM [Ca2+]o producing almost complete relaxation. Relaxations were dependent on a functional endothelium, and were inhibited by the negative allosteric CaSR modulator Calhex-231
CaSR activation also induced NO production in freshly isolated endothelial cells (ECs) in experiments using the fluorescent NO indicator DAF-FM.
Pre-treatment with inhibitors of large (BKCa) and intermediate (IKCa) Ca(2+)-activated K(+) channels (iberiotoxin and charybdotoxin), and Kv7 channels (linopirdine) also reduced [Ca(2+)]o-induced vasorelaxations.
These findings indicate that stimulation of CaSRs induces endothelium-dependent vasorelaxations which are mediated by two separate pathways involving the production of NO and activation of IKCa channels. NO stimulates PKG leading to BKCa activation in vascular smooth muscle cells, whereas IKCa activity contributes to endothelium-derived hyperpolarisations.
Ishioka et al 1999
Suggested that the endothelial relaxations were controlled by perivascular neurones
Yang et al 2005
Suggest that via TRPV4 receptors in the endothelium
In chronic hypoxic pulmonary hypertension, Yang and coworkers identified TRPV4 channels as an obligatory calcium entry pathway that is upregulated. In mouse mesenteric arteries, TRPV4 activity is favoured by the hypoxic insult that is associated with an increased Ca2+response in endothelial cells upon agonist stimulation, contributing to a potentiated EDH-mediated dilation.
Schepleman et al 2016
These findings support the use of calcium supplements in the diet to promote vascular relaxations. Their study showed that increased calcium, increases the sensitivity to contractility, augumenting against agonist induced constrictions, but we know these not to be true now because small resistance vessels like mesenterics regulate BP and these are relaxants
Fryer et al 2007
Calcimmimetic was prescribed to uraemic rats and their findings had acute hypertension but followed by hypotension
Calcium supplements Sun et al 2017
The use of calcium supplements in the diet is controversial because some people say it is beneficial. Some meta-analyses have described the beneficience of it however, they showed that overall it did not make a difference to the amount of vascular tone. This can be attributed to the fact that it causes such a small effect
