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How does decrease in Mg++ effect pTH? FA said decrease in Mg causes decrease in pTH.
Can anyone explain why?
Can anyone explain why?
Pth
- Thread starter Lonely Sol
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Mg is like a cofactor for PTH secretion in parathyroid chief cells. The adneyl cyclase is magnesium dependent for cAMP generation related to PTH release.
Low Mg stimulates PTH release
Very low Mg inhibits PTH release
Low Mg stimulates PTH release
Very low Mg inhibits PTH release
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Lonely Sol, I posted this on this forum about two months ago:
Vetter T, Lohse MJ. Magnesium and the parathyroid. Institute for Pharmacology and Toxicology, Würzburg, Germany. Curr Opin Nephrol Hypertens. 2002 Jul;11(4):403-10.
I just read the above article on PubMed. I recommend the read, however it's very long, so I'll summarize the mechanism below. By the way, I've read on some forums/threads that Mg2+ is a cofactor for cAMP, which is blatantly wrong. Mg2+ is a cofactor for the production of cAMP, not for the actual molecule itself.
Firstly, Mg2+ and Ca2+ act on the same negative feedback receptor on parathyroid chief cells. The receptor is called CaR. Magnesium is considered a partial agonist because it has 2-3x lesser affinity for CaR than calcium (both Ca and Mg are group2 alkali metals, so it's reasonable that they'd both bind given their 2s electrons).
The activation of CaR induces G-protein activity via both G-alpha-i and G-alpha-q cascades (if you don't know what that means, the chart on the bottom of p.263 in FA runs you through the different G-protein pathways), thereby causing transient cytoplasmic calcium influx, activation of phospholipase-A2, decreased cAMP activity and subsequent inhibited release of PTH. It is the combination of both G-alpha-i and G-alpha-q proteins, as stimulated by CaR, that is required for inhibition of PTH release.
As serum [Mg2+] decreases, CaR activation decreases and PTH secretion increases. This mechanism represents the inverse relationship that we'd expect for both the calcium-PTH relationship as well as the Mg-PTH one.
So far so good.
However, when serum [Mg2+] falls below 0.5mM, the inverse relationship no longer holds and PTH release decreases. This is known as the "paradoxical block of PTH secretion."
As long as [Mg2+] is > 0.5mM, there will always be some degree of Mg2+ binding to CaR, because even though Mg2+ is only a partial agonist of the receptor (decreased Vmax), the receptor's affinity for Mg2+ is still high (low Km).
Now, even though Mg2+ binding to CaR induces inhibitory effects on PTH secretion, its binding at baseline quantities maintains functionality of the PTH-inhibitory cascade, so in the "absence" of Mg2+ (<0.5mM), CaR loses functionality, but in such a fashion that it is constitutively activated, rather than non-signalling.
Therefore, with hypomagnesaemia reaching serum [Mg2+] < 0.5mM, constitutive CaR activity inhibits PTH secretion. This explains why some patients with hypocalcaemia are refractory to Tx with Ca2+ and vitamin D; only restoration of serum Mg2+ will restore serum [Ca2+] when the patient is dual hypocalcaemic and magnesaemic.
I hope that helps. As I said up above, I've read different mechanisms across random forum posts, so I had to go to PubMed to get information that's peer-reviewed.
~Phloston
Vetter T, Lohse MJ. Magnesium and the parathyroid. Institute for Pharmacology and Toxicology, Würzburg, Germany. Curr Opin Nephrol Hypertens. 2002 Jul;11(4):403-10.
I just read the above article on PubMed. I recommend the read, however it's very long, so I'll summarize the mechanism below. By the way, I've read on some forums/threads that Mg2+ is a cofactor for cAMP, which is blatantly wrong. Mg2+ is a cofactor for the production of cAMP, not for the actual molecule itself.
Firstly, Mg2+ and Ca2+ act on the same negative feedback receptor on parathyroid chief cells. The receptor is called CaR. Magnesium is considered a partial agonist because it has 2-3x lesser affinity for CaR than calcium (both Ca and Mg are group2 alkali metals, so it's reasonable that they'd both bind given their 2s electrons).
The activation of CaR induces G-protein activity via both G-alpha-i and G-alpha-q cascades (if you don't know what that means, the chart on the bottom of p.263 in FA runs you through the different G-protein pathways), thereby causing transient cytoplasmic calcium influx, activation of phospholipase-A2, decreased cAMP activity and subsequent inhibited release of PTH. It is the combination of both G-alpha-i and G-alpha-q proteins, as stimulated by CaR, that is required for inhibition of PTH release.
As serum [Mg2+] decreases, CaR activation decreases and PTH secretion increases. This mechanism represents the inverse relationship that we'd expect for both the calcium-PTH relationship as well as the Mg-PTH one.
So far so good.
However, when serum [Mg2+] falls below 0.5mM, the inverse relationship no longer holds and PTH release decreases. This is known as the "paradoxical block of PTH secretion."
As long as [Mg2+] is > 0.5mM, there will always be some degree of Mg2+ binding to CaR, because even though Mg2+ is only a partial agonist of the receptor (decreased Vmax), the receptor's affinity for Mg2+ is still high (low Km).
Now, even though Mg2+ binding to CaR induces inhibitory effects on PTH secretion, its binding at baseline quantities maintains functionality of the PTH-inhibitory cascade, so in the "absence" of Mg2+ (<0.5mM), CaR loses functionality, but in such a fashion that it is constitutively activated, rather than non-signalling.
Therefore, with hypomagnesaemia reaching serum [Mg2+] < 0.5mM, constitutive CaR activity inhibits PTH secretion. This explains why some patients with hypocalcaemia are refractory to Tx with Ca2+ and vitamin D; only restoration of serum Mg2+ will restore serum [Ca2+] when the patient is dual hypocalcaemic and magnesaemic.
I hope that helps. As I said up above, I've read different mechanisms across random forum posts, so I had to go to PubMed to get information that's peer-reviewed.
~Phloston
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Wow..Thanks so much! Appreciate it...They better have a pTH and Mg++ question on my test cuz I will be ready to kill it!!
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Well explained. I just want to add that Mg, along w/ Ca, activate CaSR on chief cells of parathyroid, when CaSR is activated, PTH secretion is inhibited. This explains the difference in PTH secretion when Mg is low vs super-low.
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Low magnesium causing hypoparathyroidism is definitely a question from one of the NBMEs that you can buy online. It most likely was in the STEP 1 test question pool at one point in the past.
