[Lotus]

Estrogen, 17β-estradiol (E2), has been shown to modulate the activity of ion channels in a diverse range of epithelial tissues. The channel activation or inhibition responses to E2 are often rapid, occurring in seconds to minutes, independent of protein synthesis and gene transcription ('non-genomic' response). These rapid effects of E2 require activation of specific protein kinases or changes in intracellular calcium and pH which in turn modulate the conductance, open probability or number of channels in the plasmamembrane.

Why are calcium ion channels important to breast growth?, simple.........rapid synthesis. Sorry for the technical tour here, it makes sense to me, if that makes any sense. Granted, this connection of Ca(2+) aka-calcium in rapid cascade is remarkable, to pair it with the biosynthesis of hormones is um, daring to say the least, is it on anybody's radar in relation to NBE?, I dunno.

lol......wait till I bring up the " Human aldo-keto reductases (AKRs) " it's a major discovery (I think).

....depolarization and repolarization of sodium and calcium ion channels, phew!!!! Estradiol has a direct effect on G-coupled protein recepotrs, besides the ion channels.

If second messenger are still new to you (or complicated) it's worth learning more about them. How would (does) second messenger fit into NBE?........I'd start with hormone biosynthesis, which in layman's term goes something like this.

1) cell diffusion (hormones passes through the cell membrane)
2) picks up the second messager
3) second messenger moves into the nucleus
4) completion (synthesis) of DNA (activation) —> new growth..........(aka-boob growth)

Now, I've passed over several key points of synthesis, but, hopefully you get the idea.

Second messengers are:

Forskolin
Calcium

A couple new one's

Zinc (long term activation, not from cascade)
Caffeine (hot damn)
(Possibly- manganese)....think pineapple

One other note: adrenalin makes hormone receptors more sensitive, guess the body builders already know this. I think NBE stacking makes sense though, as an example, say immediately after a fitness routine, NBE supplementation should commence, Imo it would follow: (when blood flow and heart rate are peak)

Pre-workout: Take anti-androgen

Post work out: MSM, E2/Phytoestrogens, pro-aromatase, calcium, ATP (astaxanthin), a few slices of pineapple, hydration, I might be missing some, feel free to add to the post work out routine.

As listed, second messengers improve the biosynthesis of hormones, so does ATP (Adenosine triphosphate, and Astaxanthin works quite well for this ), G protein-coupled estrogen receptors (GPER), activation of GPER comes from estrogen, which is the result of adenylyl cyclase and cAMP-dependent signaling.

Cell signaling
http://users.rcn.com/jkimball.ma.ultrane...Messengers

Imo, second messengers are an aromatase for cell bio-synthesis. In other words, first messengers are about cell diffusion, while second messengers boost the intercellular action for DNA syntheses (or cell reaction).

Forskolin is supplement example of a second messenger. Calcium is a second messenger too, and underestimated for NBE. Btw, boosting vitamin D and calcium upregulates ovarian aromatase.

Second messengers are intracellular signaling molecules released by the cell to trigger physiological changes such as proliferation, differentiation, migration, survival, and apoptosis. Secondary messengers are therefore one of the initiating components of intracellular signal transduction cascades. Examples of second messenger molecules include cyclic AMP, cyclic GMP, inositol trisphosphate, diacylglycerol, and calcium. The cell releases second messenger molecules in response to exposure to extracellular signaling molecules—the first messengers. First messengers are extracellular factors, often hormones or neurotransmitters, such as epinephrine, growth hormone, and serotonin. Because peptide hormones and neurotransmitters typically are biochemically hydrophilic molecules, these first messengers may not physically cross the phospholipid bilayer cell membrane to initiate changes within the cell directly—unlike steroid hormones, which usually do. This functional limitation necessitates the cell to devise signal transduction mechanisms to transduce first messenger into second messengers, so that the extracellular signal may be propagated intracellularly. An important feature of the second messenger signaling system is that second messengers may be coupled downstream to multi-cyclic kinase cascades to greatly amplify the strength of the original first messenger signal.[1][2] For example, Ras.GTP signals link with the Mitogen Activated Protein Kinase (MAPK) cascade to amplify the allosteric activation of proliferative transcription factors such as Myc and CREB. (Wiki) https://en.m.wikipedia.org/wiki/Second_messenger_system

Interesting in that calcium supplementation is suggested when taking PM, I wonder if they new that calcium improves cell biosynthesis, or was it from PM lowering the parathyroid?, hmmmm.

Anyways, The daily recommended is 1000 mg to 1200 mg, although topping out at 2500 mg, certain restrictions (interactions) need to be observed though, (check with your doctor) e.g calcium channel blockers. Carbs increase the absorption of calcium while coffee decreases it (MF'er)

Here is some excellent info on second messengers:

Second Messenger
http://users.rcn.com/jkimball.ma.ultrane...ml#IP3_DAG

Bottom line, here's one example of thinking inside the box (the cell) lol makes sense. Meaning looking at cell diffusion and how boosting the calcium signal (via calcium ion channels) improves the DNA synthesis of NBE/Hrt, just my opinion on that part though.

Calcium
http://umm.edu/health/medical/altmed/supplement/calcium

Dopamine as a Prolactin (PRL) Inhibitor
http://press.endocrine.org/doi/full/10.1....22.6.0451

Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation.

The critical role of calcium in exocytosis, termed the“ stimulus-secretion coupling” hypothesis, has been long recognized. Calcium is central to all aspects of exocytosis, including rapid fusion and unloading of the vesicles as well as recruitment and translocation of loaded vesicles. Resting levels of cytoplasmic calcium within the neuron are approximately 0.1 μm and can rise to 5–10μ m upon arrival of action potentials (19). Calcium influx occurs through voltage-gated calcium channels and leads to fusion of the synaptic vesicles with the plasma membrane and release of their content to the extracellular space. This is a much faster process than the relatively slow release of peptide or protein hormones from endocrine cells. - See more at: http://press.endocrine.org/doi/full/10.1...cduVf.dpuf


Protein-protein interactions in neurotransmitter release.
http://www.ncbi.nlm.nih.gov/m/pubmed/10683521/

The arrival of a nerve impulse at a nerve terminal leads to the opening of voltage-gated Ca(2+) channels and a rapid influx of Ca(2+). The increase in Ca(2+) concentration at the active zone from the basal level of 100-200 mM triggers the fusion of docked synaptic vesicles, resulting in neurotransmitter release. A large number of proteins have been identified at nerve terminals and a cascade of protein-protein interactions has been suggested to be involved in the cycling of synaptic vesicle states. Functional studies in last half decade on synaptic-terminal proteins, including Ca(2+) channels, have revealed that the SNARE core complex, consisting of synaptobrevin VAMP, a synaptic vesicle-associated protein, syntaxin and SNAP-25, synaptic membrane-associated proteins, acts as the membrane fusion machinery and that proteins interacting with the SNARE complex play essential roles in synaptic vesicle exocytosis by regulating assembly and disassembly of the SNARE complex.

Steroids. 2012 Aug;77(10):918-23. doi: 10.1016/j.steroids.2012.02.017. Epub 2012 Mar 5.
Estrogen regulation of epithelial ion transport: Implications in health and disease.
Saint-Criq V1, Rapetti-Mauss R, Yusef YR, Harvey BJ.
Author information


Abstract
Estrogen, 17β-estradiol (E2), has been shown to modulate the activity of ion channels in a diverse range of epithelial tissues. The channel activation or inhibition responses to E2 are often rapid, occurring in seconds to minutes, independent of protein synthesis and gene transcription ('non-genomic' response). These rapid effects of E2 require activation of specific protein kinases or changes in intracellular calcium and pH which in turn modulate the conductance, open probability or number of channels in the plasmamembrane. Estrogen has also been shown to affect the expression of ion transporters over days ('genotropic' response) causing long-term sustained changes in transepithelial ion transport. It is now accepted that so called non-genomic responses are not stand-alone events and are necessary to prime the latent genomic response and even be critical for the full latent response to occur. In a number of epithelia the non-genomic and genotropic responses to estrogen are sex-specific and variable in potency and sensitivity to E2 depending on the stage of the estrous cycle. Of increasing interest is the effect these rapid and latent actions of E2 on ion transporters have on the physiological functions of epithelia. For example, estrogen regulation of a class of voltage-gated K(+) channels (KCNQ1) can determine the rate of Cl(-) secretion in the intestine. In whole-body terms, the combined effects of estrogen on a variety of ion channels which control fluid and electrolyte transport in the kidney, intestine and lung may be necessary for endometrial expansion and implantation of the blastocyte.
Copyright © 2012 Elsevier Inc. All rights reserved.

Curr Drug Targets. 2001 Dec;2(4):401-22.
The Ca2+-activated K+ channel of intermediate conductance: a molecular target for novel treatments?
Jensen BS1, Strøbaek D, Olesen SP, Christophersen P.
Author information

Abstract
This review discusses the Ca2+-activated K+ channels of intermediate conductance (IK channels), and their historical discovery in erythrocytes, their classical biophysical characteristics, physiological function, molecular biology as well as their role as possible molecular targets for pharmacological intervention in various diseases. The first described Ca2+-activated K+ channel ever - the so-called Gard6s channel from human erythrocytes--is an IK channel. The "I" denominates the intermediate conductance that distinguishes the IK channels from the related Ca2+-activated K+ channels of small (SK) or large (BK) conductance. The recent cloning of the human IK channel gene (KCNN4) enabled a detailed mapping of the expression in various tissues. IK channel expression is found predominantly in cells of the blood, in epithelia and endothelia. An important physiological role of IK channels is to set the membrane potential at fairly negative values and thereby to build up large electrical gradients for the passive transport of ions such as Cl- efflux driving water and Na+ secretion from epithelia, and Ca2+ influx controlling T-lymphocyte proliferation. The molecular cloning of IK and SK channels has revealed that both channels gain their Ca2+-sensitivity from tightly bound calmodulin (CaM). The IK channel is potently blocked by the scorpion toxin charybdotoxin (ChTx) and the antimycotic clotrimazole (CLT). CLT has been in clinical trials for the treatment of sickle cell disease, diarrhea and ameliorates the symptoms of rheumatoid arthritis. However, inhibition of cytochrome P450 enzymes by CLT limits its therapeutic value, but new drug candidates are entering the stage. It is discussed whether pharmacological modulation of IK channels may be beneficial in sickle cell anemia, cystic fibrosis, secretory diarrhea, craft-versus-host disease and autoimmune diseases.