[Laurentiu]

The sympathetic effects of the heart muscle is stimulated through activation of G(s) protein, 2nd messenger pathways. Which of the following is an accurate step in this type of pathway signaling?

A. IP3 is released by the protein kinase A.
B. G(s) directly stimulates the production of cAMP. from ATP.
C. Adenylyl cyclase activates protein kinase A.
D. cAMP phosphorylates several downstream targets.
E. Ligand binding leads to GDP replacement by GTP

 

[rasheed]

First of all we have to recognize which receptor the question is talking about. Heart muscles contain mainly Beta one receptors when it comes to sympathetic stimulation. Alpha receptors are mainly on blood vessels.

Ok now that we know that the question is talking about beta receptors then next we have to recognize which signaling pathway is associated with beta receptors. This table helps http://www.usmle-forums.com/usmle-step-1-bits-pieces/774-g-protein-coupled-receptors-table.html

From that table we see that beta receptors use the Gs signaling pathway.

Option A is incorrect because IP3 is not released by Protein kinase A it's the reverse and even if it is grammatically correct then that's the Gq pathway not the Gs pathway.

Option B is incorrect because G proteins that directly stimulates the production of cAMP (without adenyl cyclase) do not exist.

Option C is incorrect because adenylyl cyclase stimulate production of cAMP not Protein Kinase A

Option E is incorrect because that's the mechanism associated with ligands such as nitric oxide, ANF, and others that culminate in cGMP activation.

So we are left with option D which I think is the correct answer if we look back at the Gs pathway and see how it works.

 

[Laurentiu]

pathway signaling

The correct answer is E .

Took me a long time to figure out and a lot of reading. It is notso much about the receptors , is about signaling.

There are 2 parts for the answer:

1.GTP displaces GDP and diffuses away within the membrane to activate adenylyl cyclase , which converts ATP into cAMP, which activates PKA which phosphorilates down stream targets .

2.When the GTP is hydrolized to GDP the beta and gamma subunits re-associate with a G (s) protein coupled receptor.

 

[rasheed]

The correct answer is E .

Took me a long time to figure out and a lot of reading. It is notso much about the receptors , is about signaling.

There are 2 parts for the answer:

1.GTP displaces GDP and diffuses away within the membrane to activate adenylyl cyclase , which converts ATP into cAMP, which activates PKA which phosphorilates down stream targets .

2.When the GTP is hydrolized to GDP the beta and gamma subunits re-associate with a G (s) protein coupled receptor.

Nice work,
But now you should tell us why choice D is incorrect

 

[Laurentiu]

pathway signaling

Nice work,
But now you should tell us why choice D is incorrect

G proteins are so-called because they bind the guanine nucleotides GDP and GTP. They are heterotrimers (i.e., made of three different subunits) associated with

• the inner surface of the plasma membrane and
• transmembrane receptors of hormones, etc. These are called G protein-coupled receptors (GPCRs).

The three subunits are:

• Gα, which carries the binding site for the nucleotide. At least 20 different kinds of Gα molecules are found in mammalian cells.
• Gβ
• Gγ

How They Work

• In the inactive state, Gα has GDP in its binding site.
• When a hormone or other ligand binds to the associated GPCR, an allosteric change takes place in the receptor (that is, its tertiary structure changes).
• This triggers an allosteric change in Gα causing
• GDP to leave and be replaced by GTP.
• GTP activates Gα causing it to dissociate from GβGγ (which remain linked as a dimer).
• Activated Gα in turn activates an effector molecule. In a common example (shown here), the effector molecule is adenylyl cyclase - an enzyme in the inner face of the plasma membrane which catalyzes the conversion of ATP into the "second messenger" cyclic AMP (cAMP) [More].

Activated Gα is a GTPase so it quickly converts its GTP to GDP. This conversion, coupled with the return of the Gβ and Gγ subunits, restores the G protein to its inactive state.

Hopefully this will clarify more

 

[khanar]

G proteins are so-called because they bind the guanine nucleotides GDP and GTP. They are het....... this will clarify more

Yes, that's really explains how choice E is the correct answer but as Rasheed is saying. You should tell us why choice D is incorrect?

 

[Androide89]

choice d is wrong because cAMP doesn't directly phosphorylate targets, cAMP merely activates protein kinase A, protein kinase A is what does the phosphorylation

 

[Dr_Kal_El]

WOW, i'm gonna be honest, i'm starting to freak out! I don't remember any of THIS! whats even scarier is that I don't even remember where I studied this! OMG I'm sooooo dead!

***WHERE IS THIS SECOND MESSENGER SIGNALING STUFFF*** ARRRRRRRRRRRRRGHHHHHHHH

 

[Laurentiu]

pathway signaling

WOW, i'm gonna be honest, i'm starting to freak out! I don't remember any of THIS! whats even scarier is that I don't even remember where I studied this! OMG I'm sooooo dead!

***WHERE IS THIS SECOND MESSENGER SIGNALING STUFFF*** ARRRRRRRRRRRRRGHHHHHHHH

Biochemistry/Pharmacology:

There are 3 types of G proteins :
Gq
Gs
Gi.

Gq proteins connects receptors H1,alfa1 , V1,M1,M3 to phospholipase C which acts on lipids to produce Phosphatidyl inositol 4,5 biphosphate (PIP2) which in turn act on 2-nd messanger IP3 (Inositol 1,4,5, triphosphate) and 2-nd messanger DAG (Diacylglycerol) .

IP3 increase Calcium in smooth muscle.
DAG( Diacylglycerol) acts on protein kinase C .

Gs proteins connects the receptors beta 1, beta2 , D1 , H2 , V2 to adenylyl cyclase which transforms ATP in cAMP which stimulates (Gs) 2-nd messanger Protein kinase A .

Gi proteins connects the receptors M2, alfa2 , D2 with adenylyl cyclase through cAMP (Gi) which inhibits Protein kinase A .

Hopefully this will clarify the issue .

 

[hana]

choice d is wrong because cAMP doesn't directly phosphorylate targets, cAMP merely activates protein kinase A, protein kinase A is what does the phosphorylation

100% agreed! when a question such as this one asks about details we must pay attention to choose the most precise answer.pr.k.A is responsible for "several" phosphorylation reactions. as androide89 said CAMP only works on PRKA

 

[im99]

beta 1 and beta 2 Gs mechanism?

heyy.. can anybody clear this doubt..
both beta 1 and beta 1 work via Gs receptors.. that is by increase in cAMP.. cAMP causes relaxation.. then how come beta 1 causes contraction ( increase heart rate etc) and beta 2 cause relaxation..

 

[chulady]

E

The sympathetic effects of the heart muscle is stimulated through activation of G(s) protein, 2nd messenger pathways. Which of the following is an accurate step in this type of pathway signaling?

A. IP3 is released by the protein kinase A.
B. G(s) directly stimulates the production of cAMP. from ATP.
C. Adenylyl cyclase activates protein kinase A.
D. cAMP phosphorylates several downstream targets.
E. Ligand binding leads to GDP replacement by GTP

THe answer should be E.

When ligand bind on E/C receptor site lead to Gs alpha (I/C site)active ( GDP change to GTP), and GTP bind at Gs alpha which lead to conformational changes of receptor and activate adenylase cyclase.

 

[earthpole]

good question!! thanx

 

[patelMD]

WOW, i'm gonna be honest, i'm starting to freak out! I don't remember any of THIS! whats even scarier is that I don't even remember where I studied this! OMG I'm sooooo dead!

***WHERE IS THIS SECOND MESSENGER SIGNALING STUFFF*** ARRRRRRRRRRRRRGHHHHHHHH

Look in FA. There is also a nice mnemonic given "qiss and qiq till you're SIQ of SQS ''

Starts with Alpha, Beta, etc. and what the receptors are coupled to! :happy:

 

[harlesmd]

heyy.. can anybody clear this doubt..
both beta 1 and beta 1 work via Gs receptors.. that is by increase in cAMP.. cAMP causes relaxation.. then how come beta 1 causes contraction ( increase heart rate etc) and beta 2 cause relaxation..

Because it works in different cell type and different mechanism
Beta-1 receptor in cardiac muscle cells : increased cAMP will activate protein kinase A, protein kinase A will phosphorylate the ligand gated Calcium Channel (activating the calcium channel --> increasing Ca2+ conductance).
In SA node, increased Ca2+ conductance will increase the slope of phase 4 and increase the heart rate
In ventricular muscle, increased Ca2+ conductance will increase the contractility of muscle cells.

Beta-2 receptor in vascular smooth muscle cells : increased cAMP will activate protein kinase A, protein kinase A will phosphorylate myosin light chain kinase (inactivating the enzyme) so the myosin light chain won't be phosphorylated and won't bind to actin. It will cause the relaxation of smooth muscle.

Hope it clarifies this.

 

[im99]

thank you so much. got it now. really nice explanation.