The Very Fine Line

Sorry about the lapse in posts. Harry Potter. I know. Don't judge me.

Sometimes with pharmaceuticals, there is a very fine line between treating a condition and causing a problem. This is especially true for treatments on the cellular level. Recently, Avandia and Actos, drug treatments for type II diabetes, have faced an impending ban by the FDA. They both belong to a class of drugs called thiazolidinediones. Thiazolidinediones act on peroxisome proliferator-activated receptors or PPARs, which, once bound to a ligand such as a thiazolidinedione or a fatty acid, dimerize with another receptor and act as a transcription factor on the DNA. Read the Wikipedia article if you want the mechanics of how exactly they treat diabetes cause i'm not going to summarize it for you. No sir.

These two drugs, when taken over a 26 month period, cause a 1 in 50 chance of heart failure. That, my friends, is not good. They seem to cause fluid retention. With 7 million people taking the US, you can guess that this spells bad news. It seems that the question must be asked: With billions of dollars being funneled into the development, testing, and marketing of a drug, how did something like this just slip by? Okay, big pharma, lets see you smooth this one over.

The One-Ion show in Cells

...is calcium. Now, if you were to talk to an average person about calcium, they would talk your arm off about how it strengthens bones and teeth and whatnot. Years and years of propaganda by doctors and Tums commercials have definitely taken their toll on society. However, calcium is not just important for organisms to function as a whole; on the individual cellular level, calcium is crucial for a whole slew of activities. Calcium is a second messenger. Let's say that you have a signaling molecule that cannot pass through the plasma membrane. Oh crap, how do we get the message to the cytoplasm so the cell can respond? Well, that is where second messengers come in quite handy. That hormone will bind to a transmembrane receptor on the extracellular face of the plasma membrane. The response will be transmitted to the protein's intracellular face, which will begin a signal transduction cascade of second and third etc. messengers. In this diagram, calcium is a tertiary messenger, but you get the picture. I trust you.

Here are two of the most common examples of calcium in signaling: Muscle contraction and exocytosis. Let's say....that you decide to kick your friend in the shins because he totally just called your mom a strumpet. Your brain has a hormonal orgy, which results in an electrical signal being sent straight to your leg. The axons of your motor neurons form a gap junction with your muscle. When the signal reaches your motor neurons, acetylcholine is released, causes a depolarization of the muscle fiber membrane, which travels into tubules into the muscle fiber. This action potential causes the sarcoplasmic recticulum to release calcium into the muscle fiber. Calcium binds to troponin, which causes the tropomyosin to move and expose the filament so myosin can attach and cause contraction. I just reviewed BIO 101 for you people. Be grateful.

That is more a physiological role. A cellular role of calcium is in exocytosis. Calcium is necessary for vesicles to fuse with the plasma membrane. They bind to a special SNARE proteins, which allow vesicles to fuse with their specific targets. Each vesicle has a v-snare on its surface that can interact with a specific t-snare on the target membrane. Calcium binds to the v-snare, allowing the two snares to interact, allowing the vesicle to get close enough for vesicle fusion with the target membrane.

There are also tons of different proteins that require calcium to function. Anything starting in cal- really. Calnexin and calreticulin, which are found in the ER and aid in the retention of improperly folded proteins by binding to the protein's oligosaccharide tag. Calmodulin a protein that interacts with certain kinases (called CaM-kinases). Calmodulin is activated by binding to calcium, and in its activated form, it binds to these kinases which go on to phosphorylate other proteins. This is another way that ion concentration in the cell can directly influence the processes inside the cell.

The calcium is so integral to cell functioning that it is actively pumped out of the cystol. Calcium concentration is kept at 2x10-7 M in the cell, almost a thousand times lower that the extracellular space. This is accomplished by pumps with use ATP to pump it outside of the cell, into the sarcoplasmicrecticulum (in muscle cells), into a mitochondrion or into the endoplasmic recticulum. Chelating proteins also reduce intracellular calcium levels.

You don't see that in milk ads.

Cell Communication is Raising the Bar

In order for cells to organize themselves into complex tissues so you can yap away on your cell phone, they need to communicate too. There are three commonly accepted forms of intercellular communication (see picture because my explanation will probs confuse you; i'm a visual learner too). There's paracrine signaling, in which a cell will release a chemical messenger to communicate will NEARBY cells. Nearby is the key here, people. Then, there is synaptic signaling, in which a neurotransmitter is used to communicate an electrical signal from one neural axon to another neural dendrite (or a muscle cell or whatevs else). Not pictured (so stay with me here) is cell surface-surface communication. That is where specific receptor proteins on one cell interact with signal proteins on the surface of another cell during cell-cell contact. This induces a response in the signal-er the receptor or both.

Those are all short distance signaling. Long-distance signaling is called endocrine signaling, which uses hormones to communicate messages to specific tissues or cells in the body. I mean, your pancreas can't just pick up a tin can and say "Liver, WTF? Take up some of this goddamn glucose and convert it into glycogen before you fuck everyone's shit up." No, a message as poignant and critical needs an intricate system of communication, not some retard 19th century P.O.S.


But what if the cell is developing? What if this communication is a one time thing which is necessary for beginning an essential cascade of signals during tissue development? Well, Valadi and Ekström may have discovered a really cool piece of info. They discovered that some exosomes actually carry mRNA and smaller types of RNA. When these exosomes are introduced to cells of the same type, the cells translate the mRNA into protein. This has a huge implication in an array of medical fields from cancer treatment to gene therapy. Imagine if a cancer cell could be forced into apoptosis? The exosomes are cell specific, so toxic treatments like taxol and such would be a thing of the past. Cool shit, eh?

The Sweetest Organelle

My favorite organelle by far is the mitochondrion. I mean, come on people, here is an organelle that we just picked up on the way to being a eukaryote. 'Hey archaebacteria, wanna supply me with energy in a symbiotic relationship?' 'Fuck yeah, man.' That probably what it was like 2 billion years ago, when eukaryotes were getting sick of dealing with all the competition and decided to develop organelles, aka, kick some major ass on an evolutionary scale. As the years progressed, the relationship between cell and symbiot became more intertwined. Today, many, if not most, of the proteins required for the citric acid cycle and oxphos are encoded in the cell's genome. The mRNA is translated by free ribosomes, which then must be transported into the mitochondria. However, the mitochondria refuse to give up their independence completely. They still have their own genome (although it is greatly reduced) and their own ribosomes. They are not replicated like normal organelles, but undergo a form of binary fission when the energy needs of the cell increase. They are usually pictured as little ovals, but that is just the glam of cell bio textbooks. Mitochondria can change shape and wrap around cellular structures in order to supply ATP where it is most needed. DOESN'T THAT FUCKING ROCK?!?

It does. You know it.

However, the coolest aspect of mitochondria is its role in apoptosis.

Surf's Up

Calcium is the shit when it comes to cell messages. It interacts with a ton of things in the cell, such as allowing vesicles to fuse with the membrane in exocytosis, binding to calmodulin, binding to myofibrils in muscle contraction and lots of other really important things. I found this sweet article in JGP about calcium waves in astrocytes.

By poking an astrocyte, Bowser and Khakh induced a wave of calcium that perpetuated around 200 microns from the source of the mechanical stimulus. They used Fluo-3 to track the calcium wave and then analyzed the images to make the sweet figures above.

Then they asked the obvious question, what propagates these waves? I mean, unless you're a veggie, there's a lot of shit going on in your brain. So, in order to determine whether the stimulus was intracellular or extracellular, they blocked the gap junctions, which did nothing. So then they altered the flow direction in the bath, which caused the wave to shift. Bingo people, we have extracellular stimulus. So what's doing this? ATP. After doing some glutamate receptor and P2Y1 (an ATP receptor) blocking, they found out that ATP was sending the signal to the aliens to destroy every major city in the world.

Sorry you have Diabetes, your SURs must be retarded

This is an article from Nature by Colin G. Nichols about Kir, an inward rectifying potassium channel that plays a huge part in the insulin secretion pathway. With everyone getting so fat, I figure this is handy knowledge for any biologist.


Kir is an inwardly-rectifying potassium channel that is found in pancreatic beta cells, among other places. It is usually open, but when you give into your gluttonous temptations, all the ATP that is made from the glucose in your double fudge chocolate ice cream closes the channel, causing the cell membrane to depolarize, opening calcium channels. The abundance of calcium in the cystol allows vesicles full of yummy insulin to fuse with the cell membrane, killing your sugar high before you can say bob's your uncle. When your sugar high dies a sad, sad death and intercellular ADP concentration increases, the channel opens and insulin is forced to wait in the cell until you stuff your face again.

ATP can bind to sites in the cystolic face of Kir or to the NBFs (nuclear binding folds) of SUR. Both close the slutty Kir channel. SUR is a regulatory transmembrane protein that is linked to the C-terminus of Kir. The whole pore/regulatory complex interacts with a myriad of molecules like magnesium, PIP2, and sulfonylureas.

Of course, for the 20.8 million cads in the US, sulfonylureas are only useful if you have a mutation in your SUR. For everyone else, they get to shoot up with insulin at mealtime.