User:Rincrate/sandbox

Structure and function 

Cav1.2 is widely expressed, however it is particularly important and well known for its expression in the heart where it mediates L-type currents, which causes calcium-induced calcium release from the ER Stores via Ryanodine receptors. Cav1.2 is expressed in ventricular cardiac muscle, smooth muscle, pancreatic cells, fibroblasts, and neurons. It depolarizes at -30mV and helps define the shape of the action potential in cardiac and smooth muscle.

• • should "help" in the fourth line be "helps"? Skcirdnehat (talk) 12:41, 16 November 2015 (UTC)

Regulation (this whole section is new)

The activity of CaV1.2 channels is tightly regulated by the Ca2+ signals they produce. An increase in intracellular Ca2+ concentration implicated in Cav1.2 facilitation, a form of  positive feedback called Ca2+-dependent facilitation, that amplifies Ca2+ influx. In addition, increasing influx intracellular Ca2+ concentration has implicated to exert the opposite effect Ca2+ dependent inactivation. These activation and inactivation mechanisms both involve Ca2+ binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels. Cav1.2 channels are arranged in cluster of eight, on average, in the cell membrane. When calcium ions bind to calmodulin, which in turn binds to a Cav1.2 channel, it allows the Cav1.2 channels within a cluster to interact with each other. This results in channels working cooperatively when they open at the same time to allow more calcium ions to enter and then close together to allow the cell to relax.

• 

  Due to simplicity only two Calcium channels are shown to depict clustering. When depolarization occurs, calcium ions flow through the channel and some bind to Calmodulin. The Calcium/Calmodulin binding to the C-terminal pre-IQ domain of the Cav1.2 channel promotes interaction between channels that are beside each other.

  • it may be a personal preference, but I don't think "in a study led by Dixon et al, he showed..." flows very well. Maybe something like "in a study led by Dixon et al, it was shown that..." or perhaps "Dixon et al showed that" or you could even mention that it was shown and then just let the citation show that it was a study led by Dixon without explicitly mentioning it in the article. Just a thought.Skcirdnehat (talk) 12:41, 16 November 2015 (UTC)

Clinical significance 

Mutation in the CACNA1C gene, the single-nucleotide polymorphism located in the third intron of the Cav1.2 gene - i added the the bolded part to the sentence.

Cav1.2

I like this section! I was going to suggest that you include a paragraph about what happens when this gene is disrupted, so this meets that end. Here are just a few grammatical edits:

"A large-scale genetic analysis conducted in 2008 shows the possibility that CACNA1C is associated with bipolar disorder and subsequently also with schizophrenia.Also, CACNA1C A risk allele has been associated with disruption in the brain connectivity in of patients with bipolar disorder, while not or only to a minor degree, in their unaffected relatives or healthy controls.

**The last sentence doesn't make a whole lot of sense to me. I think the idea is fine, so just rework the sentence. Do you mean that CACNA1C is a risky allele? Or is CACNA1C A a subtype domain? Also, what does "brain connectivity" mean? I think that's a little general; if it is specifically synaptic activity, just say that instead. --Theyellowdart22 (talk) 16:02, 10 November 2015 (UTC)

• • • I think what you have added is really good. You've done a good job at concisely explaining what are assuredly complex processes. That being said, I think that a few changes could be made to aid those who do not have as strong a background in this topic. For example, there are many concepts, channels, etc. that the average joe won't recognize. I like that there are lots of external links, but sometimes a little clarification about what these other topics/terms are might be helpful for the average reader. But other than that, I think everything looks awesome. Great job. 12:41, 16 November 2015 (UTC)

This is my review:

L-type Calcium Channels

History

Voltage-gated calcium channels can be found in various places such as the muscle and neuronal cells and play an important role of in many physiological events. In the 1950s, Paul Fatt and Bernard Katz identified these channels in crustacean muscle when they left Na+ ions out of their bathing medium and found that the muscle still generated action potentials. The significance of this observation was subsequently investigated in detail, using other various invertebrate tissues. In addition to the invertebrate work, mammalian tissues were soon began to be worked on too. Calcium action potentials were identified first in the mammalian skeletal and cardiac muscle and later in excitable cells. Since then, much has been found about the calcium channels on their molecular, genetic, physiological, and pharmacological properties.

L-type Calcium Channel

When the cell membrane depolarizes and an action potential is produced, voltage-gated calcium channels activate and mediate calcium influx. To date, several major types of Calcium channels have been typified according to their pharmacological properties. This includes the L-type, T-type, N-type, P/Q-type and the R-type. The L-type channel was first recognized as essential for coupling excitation to contraction in skeletal, cardiac, and smooth muscle cells. These channels are expressed in neurons and endocrine cells where they regulate a myriad of processes that include secretion synaptic transmission, gene expression, mRNA stability, neuronal survival, ischemic induced axonal injury, synaptic efficacy, and the activity of other ion channels. One of the major distinguishing characteristic of the L-type calcium channel is its sensitivity to various pharmacological agents such as dihydropyridine (DHP) agonists and antagonists.The L-type calcium channel is a heterodimeric complex is an assembly of five different sizes of channel subunits (α1, α2, β, γ, δ). A electron cryomicroscopy has been used to understand the structure of this channel in greater detail. It has two main regions that are associated with the different subunits of the channel. The first region is the heart-shaped region, where it comprises the α1,β, γ subunits and part of the δ subunit. This part of the channel is found in both the cytoplasmic and transmembrane regions of the cell. The other is the handle-shaped region, which is predominantly in the extracellular region of the cell. It comprises the α2 subunit of the channel and part of the δ subunit. There are four different subtypes of L-type channels and they are defined by their different α1 subunits and are referred to as Cav1.1-1.4. These various L-type channels differ in where they are expressed, functions and how they are activated. Some are expressed in the skeletal muscle, others in smooth muscles, and even in retina.

Cav1.1

Cav1.1 is expressed only in the skeletal muscle. The primary role of this channel is defined by acting as a voltage sensor and activates the ryanodine receptor to release intracellular calcium. Since Calcium conductance by Cav1.1 is not required for excitation/contraction coupling, the influx of calcium through the ion pore of Cav1.1 during gating is its secondary role. In a series of experiments, Numa, Beam, and colleagues, isolated excitation-contraction couple of Cav1.1. channel currents in dysgenic muscle, and found that these currents were small and activated with slow kinetics, which are consistent with native L-type currents in skeletal muscle.

The regulation of this channel involves long-term depolarization, which causes proteolysis of the α1s subunit. During a long-term depolarization, a drastic reduction in the amplitude of currents flowing through Cav1.1 channels is seen. This change in current causes a reduction in the release of calcium from the sarcoplasmic reticulum and endoplasmic reticulum, an essential step in muscle contraction.

Mutations in Cav1.1 have shown causation for two congenital muscle pathophysiologies, hypokalemic periodic paralysis and malignant hyperthermia. In a study led by Pietri-Rouxel, they infected a mouse a an alpha-1 knockout of Cav1.1 and compared it with a wildtype mouse. The results were gross atrophy reduced fiber diameter and substantially more fibrosis of the knockout mouse than the muscles of the wild type mouse.This shows that Cav1.1 ablation results in the loss of EC coupling and expression of Cav1.1 is required for maintaining muscle integrity.

Cav1.2

Cav1.2 can produce excitation-contraction coupling in dysgenic muscles in a cardiac-like manner. Calcium flux across this channel is essential to trigger muscle contraction. Due to the sequence differences in I-II intracellular linker region between Cav1.1 and Cav1.2 channels, Cav1.2 can open faster. Beam and colleagues demonstrated that these linkers;1S3-1S4 linker of Cav1.1 and Cav1.2 determined the gating phenotypes of these two L-type calcium channel by swapping the slow gating phenotype of Cav1.1; the1S3-1S4 linker, to Cav1.2 and showed that these linker regions modulated gating kinetics. Cav1.2 is expressed in ventricular cardiac muscle, smooth muscle, pancreatic cells, fibroblasts, and neurons. It depolarizes at -30mV and help define the shape of the action potential in cardiac and smooth muscle. In neurons, Cav1.2 channels play a role in regulating gene expression. The activity of Cav1.2 channels is tightly regulated by the calcium signals they produce. An increase in intracellular calcium concentration can result in Cav1.2 facilitation, a form of positive feedback called calcium-dependent facilitation, which amplifies calcium influx. In addition, increasing influx intracellular calcium concentration has also shown to exert the opposite effect, calcium dependent inactivation. These activation and inactivation mechanisms both involve calcium binding to calmodulin (CaM) in the IQ domain in the C-terminal tail of these channels. In a study led by Dixon et al., he showed that Cav1.2 channels are arranged in cluster of eight, on average, in the cell membrane. When calcium ions bind to calmodulin, which in turn binds to a Cav1.2 channel, it allows the Cav1.2 channels within a cluster to interact with each other. This results in working cooperatively when they open at the same time to allow more calcium ions to enter and then close together to allow the cell to relax. Mutations with a loss of function in Cav1.2 can cause many effects. Mutations in the pore-forming α-1 subunit of the Cav1.2 channel causes long QT, severe arrhythmia and multiple organ systems dysfunction called Timony syndrome. In a recent study, it was found that one single-nucleotide polymorphism located in the third intron of the Cav1.2 gene is linked to bipolar disorder.

Cav1.3

Cav1.3 is expressed in mainly neurons, endocrine cells and atrial myocytes. When the gene that codes for Cav1.3 channels was inactivated in a mouse, the results showed significantly slower pacemaker activity and also promoted spontaneous arrhythmia. This demonstrates that Cav1.3 channels play a major role in the generation of cardiac pacemaker activity by adding to diastolic depolarization in sinoatrial node pacemaker cells. In addition Cav1.3 channels translate sound -induced depolarization and neurotransmitter release in auditory hair cells. In a study led by Marshalling, they found that the Cav1.3 genes knocked mice showed severe impairments in dentate gyrus neurogenesis, with significantly smaller dentate gyrus volume, reduced survival of newly generated cells, and reduced neuronal differentiation. This implicates that Cav1.3 is essential for these cognitive functions.

Even though Cav1.2 and Cav1.3 channels are both expressed in excitable cells, they have very different activation thresholds. When both channels were isolated from neuronal tissues, and recorded under identical conditions, Cav1.3 channels start to activate at about -55mV, a voltage that is about 20-25mV more hyperpolarized as compared with Cav1.2. This shows us that Cav1.3 has a low-threshold activation. This channel is regulated by calcium bound calmodulin (CaM). It interacts with Cav1.3 to induce calcium-dependent inactivation (CDI), putting a halt to the influx of calcium.

Human diseases resulting from mutations of the gene that encodes Cav1.3 channel have yet to be reported. When Cav1.3 channel knockout mice were studied, they were not distinguishable from wild type, which suggests that the complete loss of homozygous Cav1.3 function would not be lethal. Even though homozygous loss of Cav1.3 individuals usually suffer from sinoatrial node dysfunction, bradycardia and sinoatrial node arrhythmia observed in Cav1.3 knockout mice disappear during exercise.

Cav1.4

Cav1.4 calcium channels are mostly involved in glutamate release from rod photoreceptors found in the retina.

Compared with other L-type calcium channels, Cav1.4 channels are activated at relatively rapidly at low activation threshold. This is an important property for the ability of photoreceptors to sustain continual glutamate release in the dark. The protein CaBP4 is a sub-family of calmodulin and modulates the Cav1.4 channel. It binds to multiple sites in the C-terminal of the alpha-1 subunit. In the Haeseleer lab they showed that in transfected cells, protein CaBP4 associates with the C-terminal domain of the Cav1.4 alpha-1 subunit, and shifted the activation of Cav1.4 at hyperpolarized voltages. These observations show that CaBP4 is important for regulation of calcium influx through Cav1.4 channels.

When mutations in Cav1.4 alpha1 subunit occurs, it results in an X-linked disorder (CSNB2) due to insufficient transmission of signals from rod photoreceptors to bipolar cells.In addition, deletion of the beta2-subunit of another component of photoreceptor L-type channel results in an altered expression of Cav1.4 and produces a phenotype that is seen in night blindness (CSNB2) patients.

Conclusion

L-type calcium channels found in various cells and are essential for excitation and contraction. In addition they regulate a processes such as the secretion of neurohormones and transmitters. They maintain muscle integrity, aid in providing vision, proper functioning of the heart and hearing. When these channels are altered or mutated in anyway, as mentioned above, can produce detrimental results. Each of the different subtypes of L-type channels have a different function unique to itself.  Even though much is understood about these channels, a greater understanding of each different subtype is needed. This will allow the pharmacodynamics of novel therapeutic drugs to be more specific when treating illnesses or diseases that relate to the malfunctioning of any of these channels. In addition, there could be more subtypes of the L-type calcium channel that have yet been discovered.

*Good summary of info, but there are a few grammatical things that are confusing. Let's just talk about it before or after class. Theyellowdart22 (talk) 23:20, 2 December 2015 (UTC)

I made a few more grammar edits. Make sure you are putting things in your own words, I found some plaigerism (using entire sentences from the journals). I know you are summarizing things, but I think you should synthesize it a little more. Theyellowdart22 (talk) 21:44, 7 December 2015 (UTC)

sorry that was still my rough draft. I thought I updated this page. But this is the updated one. Rincrate (talk) 04:15, 8 December 2015 (UTC)