Smooth muscle dialates in response to the peripheral NS relesasing neurotransmitter acetylcholine
Acetylcholine receptor is on endothelial cell, and Ach binds to it. That endothelial cell synthesizes NO which diffuses across membrane into muscle which is bound by NO receptor, which then allows smooth muscle relaxation.
The alpha subunit always binds GTP, but when there is separation and diffusion through the membrane it depends on the type of HG-protein to which protein the alpha or beta/gamma subunit will be doing the next action
In active state, beta/gamma subunit and alpha subunit separate and the beta and gamma act as a dimer
Alpha then – binds to GDP and hydrolyzes to GTP
When bound by Ach, GTP is bound by alpha subunit that makes cascading reactions that leads to hydrolysis of PIP2 in the membrane
Diffuses through cytosplasm to bind to IP3 receptors on the smooth ER.
Smooth ER serves as a storage site for calcium
Receptor opens up and allows Ca2+ channel to open and allow it into the cytosol, so intracellular calcium levels increase
The Ca2+ is immediately bound up by the calcium binding proteins, in this case called calmodulin – 4 Ca2+ opens up calmodulin structure so it can interact with other proteins
One result of this is the activation of NO synthase – so now we have increased levels of active NO synthase, and the NO synthase will convert arginine to NO.
NOTE:: All of these steps occur within the cytoplasm of the endothelial cell after Ach binds to the receptor in order to just make NO, which can diffuse across the membrane and lead to relaxation.
Activated heterotrimeric G protein turns on enzyme to cleave PIP2 in membrane
When NO Diffuses across membrane to smooth muscle cell, it also binds to receptor for NO and then from there, the signaling continues to allow the smooth muscle to relax, this is not a direct effect
Binding of NO to receptor activates an enzyme called guananyl cyclase, which converts GTP to cGMP, by removing two Pi.
cGMP, like cAMP, is an important signaling molecule
in this case, 2 bind and activate protein kinase G by binding it
many kinases have specific conformation for catalytic sites for kinase functions (phosphorylation of targets) until regulatory sites are bound and in this case, the reg. sites are bound by cGMP, and when they are bound, changes confo. Of proteins to open to catalytic sites are open and can recognize targets.
Phosphorylation of the channel inactivates it.
When inactive, Ca2+ cannot, extracellular Ca2+ channels in the plasma membrane cannot open when phosphorylated, come into EXC space form smooth muscle. Induces relaxaition, Ca2+ is required for muscle contraction, so with low Ca2+ levels, smooth muscle is forced to relax. Muscle relaxation is caused by phosphorylation of Ca2+ channel.
Eventually will be dephosphorylated by phosphatases and the smooth muscle can contract
As long as protein kinase G is active, you have relaxation of smooth muscle.
Controlled by cGMP, which is controlled by levels of NO
Cytoplasmic region between transmembrane regions 5 and 6
Exposed after ligand binding (confo change) that will interact with heterotrimeric g protein in plasma membrane
Sits in an inactive state in the membrane where the alpha subunit is bound to GDP
Difference between heterotrimeric g proteins and small g proteins is that the heterotrimeric g proteins are linked to the membrane and small g proteins are not – they are solube proteins in the cytoplasm.
3 subunits function as an inactive proteins when alpha is bound to GDP
when loop is exposed on receptor, the heterotrimeric g protein moves as a unit and binds to loop
alpha subunit underges a conformational change exposing a site for GTP binding (GEFs come in)
GTP when bound, leads to activation of heterotrimeric g protein, which separates the alpha beta/gamma subunits and the two separate subunits (alpha and beta/gamma) are activated