What is something 52% of American adults do on a regular basis? Brush their teeth? (Just kidding…78% of adults do that). The real answer is drink alcohol. Yeah. Since drinking is such a common thing, you’d think scientists would know how alcohol affects our brains. Oddly, however, alcohol’s story in the brain is still a very complicated and confusing tale.
According to Newton and Messing in their article, “Intracellular signaling pathways that regulate behavioral responses to ethanol” Some aspects of the alcohol story are being uncovered. These effects seem to somehow involve the proteins adenylyl cyclase (AC), protein kinase A (PKA), DARPP-32, fyn kinase, protein kinase C (PKC), phospholipase D (PLD), and a fun little transcription factor called CREB.
AC, PKA, and CREB
How does ethanol signal through these molecules? It seems that ethanol decreases function of a transporter protein called ENT1. Usually ENT1 would take up adenosine, but when it’s inhibited it doesn’t – a ton of adenosine builds up outside the cell. Once this happens, there is more adenosine to activate its receptor. Since adenosine’s receptor has interactions with a Gs protein, its increased activity leads to increase AC production. Increased AC in the cell leads to cAMP production and eventually signaling via PKA. PKA signaling activates CREB which is a transcription factor and can change gene regulation! Phew. What affects does this signaling have? According to mice studies, this pathway could be important in ethanol preference and self-administration. But, it seems that effects depend on brain region.
DARPP-32 and Fyn kinase
These two proteins have some interesting and rather confusing effects on our brains. PKA pathways stimulated by dopamine signaling (which is stimulated by ethanol) activate DARPP-32 by phosphorylation. DARPP-32 then goes on to inhibit a phosphatase, PP1. PP1’s usual role is to dephosphorylate NMDA receptors to decrease brain excitability. However, when it’s inhibited, NMDA receptors remain active.
Fyn acts in a similar way. Ethanol seems to allow Fyn kinase to disassociate from its regulatory scaffolding protein, RACK. Once it gets rid of RACK it can go on to do whatever it’s feelin’……which happens to be phosphorylating NMDA receptors. And, like before, NMDA receptors are activated. It is hypothesized that this NMDA activation is important in the reward and reinforcement in ethanol consumption.
PKC
Since there are many forms of PKC acting in many brain areas, its actions can get quite complicated. Mice lacking PKCγ have decreased response to the “sleepiness/decreased brain activity” typical of alcohol and they also have decreased preference for ethanol. Mice lacking PKCε also show decreased hypnotic effects and consume less ethanol. It is thought that possibly PKC could signal through GABA receptors, glycine receptors, and voltage-gated Ca2+ channels although the facts behind this are still murky.
PLD
PLD is one molecule that can directly use ethanol as a substrate. This protein’s normal function is to hydrolyze membrane phospholipids to make phosphatidic acid (PA). PA acts as a second messenger for many things including PKC, PLC, mTOR, Raf1, phosphatidylinositol 5-kinase, and others. However, in the presence of ethanol, instead of producing PA, PLD uses ethanol to produce another molecule, phosphatidylethanol (PEth). This switch-up can produce two effects: first, you don’t make PA, and second, PEth is incorporated into cell membranes to make them more fluid. Because of these, cell signaling will be altered and neurotransmitter release may be inhibited.
It seems that alcohol has some interesting effects on our brains; however, the knowledge is certainly incomplete. Alcohol seems to have very different effects on different brain areas. In fact, some signaling molecules even have opposing effects depending on brain area. So…until we figure out more….ignorance is bliss? Drink up!
Newton, P.M., Messing, R.O. (2006) Intracellular signaling pathways that regulate behavioral responses to ethanol. Pharmacology & Therapeutics 109, 227-237.
http://crystalwineglasses78.webs.com/
Hello School, Goodbye life.
http://www.iuma.be/reverse%20punch.html
Cheers!
