Beta adrenergic receptor physiology question

[hemoglobincell]

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So I've been trying unsuccessfully to figure out why the beta-2 adrenergic receptor causes vasodilation and bronchodilation. I understand that they are coupled to an increase in cAMP and activation of protein kinase A, but then all the sources I've checked have an arrow --> physiologic actions.

What I'd like to know is if anyone knows off the top of their heads why increased protein kinase A activity results in decreased intracellular [Ca++] (I'm assuming decreased [Ca++] is the ultimate effector mechanism to produce relaxation).

Finally, if increased cAMP decreases [Ca++] in the smooth muscle cell resulting in vasodilation then:

1) Why don't beta-1 adrenergic receptors, which also are coupled to an increase in cAMP, decrease contractility?
2) Why do alpha-2 adrenergic receptors, which are coupled to decrease in cAMP, cause smooth muscle contraction?

 

[Dwindlin]

So I've been trying unsuccessfully to figure out why the beta-2 adrenergic receptor causes vasodilation and bronchodilation. I understand that they are coupled to an increase in cAMP and activation of protein kinase A, but then all the sources I've checked have an arrow --> physiologic actions.

What I'd like to know is if anyone knows off the top of their heads why increased protein kinase A activity results in decreased intracellular [Ca++] (I'm assuming decreased [Ca++] is the ultimate effector mechanism to produce relaxation).

Finally, if increased cAMP decreases [Ca++] in the smooth muscle cell resulting in vasodilation then:

1) Why don't beta-1 adrenergic receptors, which also are coupled to an increase in cAMP, decrease contractility?
2) Why do alpha-2 adrenergic receptors, which are coupled to decrease in cAMP, cause smooth muscle contraction?

If I remember correctly beta-1 and 2 actually increase intracellular [Ca++] so it makes sense as to why beta-1 increases contractility. Also, alpha-2 do cause relaxation in the gut.

As to your original question, I had no good rational, so after a quick search (very quick mind you) I was able to find a couple articles that were questioning the dogma of beta-2 > Gs > +cAMP > PKA activation. It appears that there may be some Gi stimulation as well by beta-2 (which would make sense with wanting to relax smooth muscle).


Edit: Fixed some typos.

 

[Laryngophed]

cAMP inhibits activation of MLCK, preventing phosphorylation of the myosin light chain preventing it from cross-bridging with actin in the VSM, IIRC.

 

[hemoglobincell]

cAMP inhibits activation of MLCK, preventing phosphorylation of the myosin light chain preventing it from cross-bridging with actin in the VSM, IIRC.

Okay this makes sense. Since cardiac muscle does not have MLCK, it makes sense then that increased protein kinase A activity in smooth muscle (inactivating MLCK) has a different effect than in cardiac muscle (where it increases sarcoplasmic Ca2+-ATPase, causing increased storage of Ca2+ in the SR and increased contractility on the next cycle).

My only issue with this mechanism is that protein kinase A normally activates its protein products through phosphorylation. Is there any evidence that instead of inactivating MLCK that PKA may activate (directly or indirectly) MLC phosphatase? I did a quick search of the literature (wikipedia, haha) and it claims MLC phosphatase is activated by Rho kinase. This isn't the first time I've heard of Rho kinase, but I still haven't the faintest idea of what it does or how it's activated (but will research later).

 

[Jolie South]

I don't remember the exact dogma, but first aid lists out the types of receptors and what their intermediaries are. That's probably the first step to researching further. I think Costanzo might also explain in more detail (not sure though).

One of our professors had an image with all the receptors and arrows to their secondary messengers and final actions. I can look for it later.

 

[Laryngophed]

Okay this makes sense. Since cardiac muscle does not have MLCK, it makes sense then that increased protein kinase A activity in smooth muscle (inactivating MLCK) has a different effect than in cardiac muscle (where it increases sarcoplasmic Ca2+-ATPase, causing increased storage of Ca2+ in the SR and increased contractility on the next cycle).

My only issue with this mechanism is that protein kinase A normally activates its protein products through phosphorylation. Is there any evidence that instead of inactivating MLCK that PKA may activate (directly or indirectly) MLC phosphatase? I did a quick search of the literature (wikipedia, haha) and it claims MLC phosphatase is activated by Rho kinase. This isn't the first time I've heard of Rho kinase, but I still haven't the faintest idea of what it does or how it's activated (but will research later).

I think the idea is that ß2 works through PKA, not RhoK (say rock) and that makes me think there is more than one phosphorylation site on the MLCK, with one being an inhibitory site. So, ß2 is activated, turns on PKA, PKA goes nuts phosphorylating stuff and in so doing, turns off MLCK. Vessel relaxes.

That's the Cliff's notes of my understanding of the pathway. I'll defer to Constanzo or someone else who many know more than I do.

 

[swampthing6]

Okay this makes sense. Since cardiac muscle does not have MLCK, it makes sense then that increased protein kinase A activity in smooth muscle (inactivating MLCK) has a different effect than in cardiac muscle (where it increases sarcoplasmic Ca2+-ATPase, causing increased storage of Ca2+ in the SR and increased contractility on the next cycle).

My only issue with this mechanism is that protein kinase A normally activates its protein products through phosphorylation. Is there any evidence that instead of inactivating MLCK that PKA may activate (directly or indirectly) MLC phosphatase? I did a quick search of the literature (wikipedia, haha) and it claims MLC phosphatase is activated by Rho kinase. This isn't the first time I've heard of Rho kinase, but I still haven't the faintest idea of what it does or how it's activated (but will research later).

Found this in my old physio syllabus if it helps: "activates cAMP-dependent protein kinase (PKA), proteins associated with increasing cytosolic Ca2+ concentration are phosphorylated and cytosolic Ca2+ concentrations are decreased. The identification of the phosphorylated proteins is not as clear as it is for cGMP-dependent protein kinase but they are probably similar"

So no one knows for sure yet, but probably the same phosphorylated proteins that cGK acts on. Hope this helps.

 

[andie gustafson]

the mechanism is:
AMPc --> activates protein kinase A --> phosporilates the already phosporilated miosin head that was responsible for contraction --> inactivates the miosin head so that it can't be attached to the actine filament--> relaxation

 

[Redgar]

PKA has different targets in VSM vs. CM, since these cell types have different contents.

CM: PKA phosphorylates: PLB, I-Ca,L, TnI, Iks, and Ryr

VSM: PKA phosphorylates
--MLCK, which decreases its affinity for Ca/CaM, which in turn prevents it from phosphorylating MLC, and therefore prevents contraction
--K-ATP channel, opening it, leading to hyperpolarization and relaxation.
--RYR: this increases [Ca++]i, but because of the organization of VSM's SR, this it increases the frequency of calcium sparks which are not sufficient to cause contraction but are (because of the 15nm proximity to the plasma membrane) sufficient to open BK-Ca and SK-Ca potassium channels, again causing hyperpolarization.

 

[navigator]

Necromancing this question, but FYI, in addition to the answers above, alpha-2 receptors should increase smooth muscle contraction bc normally PKA inhibits MLCK activity, so decreased PKA means there's less inhibition of MLCK. Increased MLCK activity phosphorylates/activates MLC, which is able to interact with actin filaments to cause smooth muscle contraction.

Source: FA 2017 p 230

 

[apoplectic]

Necromancing this question, but FYI, in addition to the answers above, alpha-2 receptors should increase smooth muscle contraction bc normally PKA inhibits MLCK activity, so decreased PKA means there's less inhibition of MLCK. Increased MLCK activity phosphorylates/activates MLC, which is able to interact with actin filaments to cause smooth muscle contraction.

Source: FA 2017 p 230

I learned best via diagrams. Lilly’s Pathophysiology of Heart Disease, Costanzo’s Physiology and Katzung’s Pharmacology have really great diagrams reviewing these mechanisms. One is attached from each source I mentioned