Vitamin D and Intracellular Actions

00:01 Now, vitamin D is unusual in another respect.

00:05 Vitamin D acts like a hormone as I said and it is in fact a steroid hormone as some people categorize it.

00:11 However, steroid hormones move across cellular membranes at will.

00:16 They don’t have to be transported.

00:18 Vitamin D, however, has a receptor protein on the cell surface that binds to it and brings it into the cell.

00:24 This is unusual for a steroid hormone.

00:27 Vitamin D bound to the vitamin D receptor then interacts with a protein inside the cell known as the vitamin D receptor or the VDR.

00:36 The VDR is similar to the steroid hormone receptors, but in the case of the VDR, the vitamin D is actually brought to it by the vitamin D binding protein on the surface of the cell.

00:48 Vitamin D-VDR complex then goes into the nucleus and binds to hormone response elements or HREs as they're called in DNA.

00:58 The effect of this vitamin D-VDR complex binding to these elements causes genes associated with those elements to be expressed and made.

01:08 So what we can see as happening here is vitamin D is actually affecting gene expression inside of a cell as a result of movement into the cell and ultimately into the nucleus.

01:19 Vitamin D, of course, control the transcription of specific genes and it does with the process that I have just described to you.

01:26 What are these genes? Well, the genes are involved in mineral metabolism as we have seen.

01:31 And they’re also involved in immune functions that help provide for a strong and healthy immune system.

01:37 This is a different function of vitamin D than what I’ve talked about up to this point.

01:42 Vitamin D can also interfere with receptor tyrosine kinase signaling.

01:47 As I’ve talked about in another lecture, receptor tyrosine kinase signaling is very important in the process of controlling cellular division.

01:56 Because of this, vitamin D favors differentiation.

01:59 It slows the division process down and allow cells to differentiate.

02:03 It also favors the process of apoptosis or programmed cell death, in which cells that have gotten out of whack automatically commits suicide.

02:13 For this reason, vitamin D is actually important in anti-tumor properties as we can see.

02:19 Vitamin D also inhibits the process of angiogenesis.

02:23 Angiogenesis is the process whereby new blood vessels are made.

02:27 Now, new blood vessels are made by some cells that are stimulated by the production of tumor cells.

02:34 If we inhibit the production of angiogenesis, we inhibit the production of tumors and so again, vitamin D has anti-tumor properties that help to keep us healthy.

02:45 Now, calcium, as I said, inside this cell has many functions and the cell is very careful with it.

02:50 For one, it is a second messenger.

02:52 We’ve talked about second messenger in another lecture.

02:55 The second messengers convey signals that come from outside the cell and cause changes inside of the cell as a result.

03:04 Calcium is hazardous to DNA.

03:06 Too high of a calcium concentration will cause chromosomes to precipitate.

03:12 Well the last thing you want your chromosomes to do inside of a cell is to fall out of solution.

03:18 Calcium interacts as a result with proteins that keep its concentration from getting too high.

03:23 One of these proteins that's commonly used is known as calmodulin.

03:27 Now, calmodulin is a protein that is shown on the figure on the right and it’s a very flexible protein.

03:33 You can see on the figure on the left where the calmodulin has no calcium bound to it and compare that with this figure that is shown on the right that has the calcium bound to it.

03:42 You can see a change in shape that has happened.

03:45 And you can also see a little bit of those EF hands that I talked about before.

03:49 In the case of the structure on the right, EF hand is literally holding onto that calcium as you can see.

03:56 The shape change that occurs in calmodulin on binding of the calcium is the signal to other proteins inside the cell that calcium is present.

04:05 So rather than proteins interacting directly with calcium, they interact with calmodulin that has the calcium bound to it.

04:12 If they interact with the calmodulin that doesn’t have the calcium bound to it, the calmodulin is in the wrong shape and the protein knows that the cell is not signaling with calcium.

04:21 The EF hand structure, as I said, is a very important structure.

04:24 Calmodulin has two EF hand binding regions and those two EF hand binding regions each bind to one calcium ion.

04:33 Calcium can also bind to many proteins as second messenger.

04:36 So calmodulin is only one of the proteins through which calcium can exert its effects.

04:42 As I noted earlier, calcium is also the stimulus for muscular contraction.

04:47 Causing muscles to contract is a pretty important thing so we don’t want muscles contracting uncontrollably and that is managed very carefully using a specialized organelle inside the muscle cells known as the sarcoplasmic reticulum.

05:00 Yet one more function that is associated with calcium is controlling glycogen breakdown.

05:06 Now, glycogen, of course, is a very important source of glucose in our cells.

05:11 Glucose is needed for energy.

05:13 So I want to show you very briefly what happens with that.

05:16 In other lectures, I’ve talked about glycogen metabolism and I’ve talked about how glycogen metabolism is stimulated by action of a protein known as phosphorylase kinase.

05:27 Calcium affects this protein.

05:30 Calcium is, as I said, the signal for the muscles to contract and it’s stimulating glycogen breakdown.

05:36 Now, why do I mention muscle contracting and glycogen breakdown in almost the same sentence? Well, muscle contraction requires glucose and glucose is produced by glycogen breakdown.

05:47 And so, when we think about the release of calcium that happens inside of muscle cells is not only causing a muscle cell to contract but it’s also stimulating the action of phosphorylase kinase which ultimately stimulates the breakdown of glycogen to provide glucose, which is energy for the muscle cell.

06:07 Now, you can see on the figure on the right here what’s actually happening is the calcium is binding to calmodulin, the upper left part of the figure.

06:14 And calmodulin is the interacting protein that is affecting the phosphorylase kinase.

06:20 So if we look at the figure on the far left, we see fully inactive phosphorylase kinase.

06:25 Moving upwards to the upper right, we see that we have it partially active.

06:30 And the partial activation of that protein is happening as a result of calcium bound to calmodulin activating the phosphorylase kinase.

06:39 Why is it only partly active? It’s only partly active because the phosphorylase kinase has also be phosphorylated and it has to have a phosphate group attached to it to be fully active.

06:50 That happens in the process shown at the bottom.

06:53 So the cell can either go to the process to the bottom first, that is phosphorylation first, and then get the calcium added or it can start by getting the calcium added going up to the top and then get phosphorylated to get the fully active form.

07:08 What’s the difference? Well, the difference is that the top process occurs almost instantaneously, as soon as calcium is released, phosphorylase kinase is activated and glycogen breakdown happens almost instantaneously.

07:20 If you’re taking off on a race and you want to run fast, you need that glucose now.

07:25 You don’t need to wait for your hormones to release, that hormone release causes the phosphorylation.

07:32 So by having this immediate action, the phosphorylase kinase can give glucose as soon as the muscle cell actually needs it.

07:40 So, as I said, this increases the glucose concentration.

07:43 The muscle cell is happy and this also increases the ATP because glucose is what’s needed to synthesize ATP inside the cells.

07:51 Now, calcium-calmodulin can also act inside the muscle cells in a sort of a cyclic stimulatory process, in which they also bind to the endoplasmic reticulum and stimulate the release of even more calcium.

08:03 So we a sort of snowballing effect that can happen once calcium gets released.

08:09 So with this lecture, we have seen two very important and interesting fat-soluble vitamins, vitamin A which has roles in vision and also in the process of differentiation.

08:19 We’ve also seen vitamin D and its ability to modulate calcium levels in the cell as well as its ability to control gene expression and a variety of other functions necessary for multicellular organisms.