User:Linde8/sandbox

This is a simple diagram of the structure of the Large Conductance Calcium Activated Potassium Channel (BK). This channel, unlike other Potassium channels has seven transmembrane regions, where normal Potassium channels only have six.

Calcium-activated potassium channels are potassium channels gated by calcium, or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that Calcium levels inside of a cell could affect the permeability of potassium through that cell membrane. Then in 1970, Meech was the first to observe that intracellular calcium could trigger potassium currents. In humans they are divided into three subtypes Large Conductance or BK channels, which have very high conductance which range from 100 to 300 pS, Intermediate Conductance or IK channels, with intermediate conductance ranging from 25 to 100 pS, and Small Conductance or SK channels with small conductances from 2-25 pS.

Structure

Knowing the structure of these channels can provide insight into their function and mechanism of gating. They are made up of two different subunits, alpha and beta. The alpha subunit is a tetramer which forms the pore, the voltage sensor, and the calcium sensing region. This subunit of the channel is made up of seven trans-membrane units, and a large intracellular region. The voltage sensor is made by the S4 transmembrane region, which has several Arginine residues which act to ‘sense’ the changes in charge and move in a very similar way to other voltage gated potassium channels. As they move in response to the voltage changes they open and close the gate. The linker between the S5 and S6 region serves to form the pore of the channel. Inside of the cell, the main portion to note is the calcium bowl. This bowl is thought to be the site of calcium binding.

BK Channels

Though not implied in the name, but implied by the structure these channels can also be activated by voltage. The different modes of activation in these channels are thought to be independent of one another. This feature of the channel allows them to participate in many different physiologic functions. The physiological effects of BK channels have been studied extensively using knockout mice. In doing so it was observed that there were changes in the blood vessels of the mice. The animals without the BK channels showed increased mean arterial pressure and vascular tone. These findings indicate that BK channels are involved in the relaxation of smooth muscle cells. In any muscle cell, increased intracellular calcium causes contraction. In smooth muscle cells the elevated levels of intracellular calcium cause the opening of BK channels which in turn allow potassium ions to flow out of the cell. This causes further hyper-polarization and closing of voltage gated calcium channels, relaxation can then occur. The knockout mice also experienced intention tremors, shorter stride length, and slower swim speed. All of these are symptoms of ataxia, indicating that BK channels are highly important in the cerebellum.

IK Channels

Intermediate conductance channels seem to be the least studied of all of the channels. Structurally they are thought to be very similar to BK channels with the main differences being conductance, and the methods of modulation. It is known that IK channels are modulated by calmodulin, whereas BK channels are not.

IK channels have shown a strong connection to calcification in vasculature, as inhibition of the channel causes a decrease in vascular calcification. (Mechanism). Over expression of these channels has quite a different effect on the body. Studies have shown that this treatment causes proliferation of vascular smooth muscle cells. This finding has sparked further exploration surrounding these channels and researchers have found that IK channels regulate the cell cycle in cancer cells, B and T lymphocytes, and stem cells. These discoveries show promise for future treatments surrounding IK Channels. 

SK Channels

Small conductance calcium activate potassium channels are quite different from their relatives with larger conductance. The main and most intriguing difference in SK Channels is that they are voltage insensitive. These channels can only be opened by increased levels of  intracellular calcium. This trait of SK channels suggests that they have a slightly different structure than the BK and IK channels.

Like other potassium channels they are involved in hyper-polarization of cells after an action potential. The calcium activated property of these channels allows them to  participate in vaso-reguation, auditory tuning of hair cells, and also the circadian rhythm. Researchers were trying to figure out which channels were responsible for the re-polarization and after hyper polarization of action potentials. They did this by voltage clamping cells, treating them with different BK, and SK channel blockers and then stimulating the cell to create a current. The researchers found that the re-polarization of cells happens because of BK channels and that a part of the after hyper polarization occurs because of current through SK channels. They also found that with blocking SK channels, current during after hyper polarization still occurred. It was concluded that there was a different unknown type of potassium channel allowing these currents. 

It is clear that SK channels are involved in AHP. It is not clear exactly how this happens. There are three different ideas on how this is done. 1) Simple diffusion of Calcium accounts for the slow kinetics of these currents, 2) The slow kinetics is due to other channels with slow activations, or 3) The Calcium simply activates a second messenger system to activate the SK channels. Simple diffusion has been shown to be an unlikely mechanism because the current is temperature sensitive, and a diffusive mechanism would not be temperature sensitive. This is also unlikely because only the amplitude of the current is changed with concentration of Calcium, not the kinetics of the channel activation. 

Bibliography

• Brenner, R., Jegla, T. J., Wickenden, A., Liu, Y., & Aldrich, R. W. (2000). Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4. J Biol Chem 275, 6453–6461. Ghatta S, Nimmagadda D, Xu X, O’Rourke S.T. Large-conductance, calcium-activated potassium channels: Structural and functional implications. Sciencedirect. North Dakota State University. 2006. Review.  Hermann A, Sitdikova GF, Weiger TM. Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels. Biomolecules. 2015 Aug 17;5(3):1870-911.doi:10.3390/biom5031870. Review. PMID 26287261. Kaczorowski GJ, Knaus HG, Leonard RJ, McManus OB, Garcia ML. High-conductance calcium-activated potassium channels; structure, pharmacology, and function. J Bioenerg Biomembr. 1996 Jun;28(3):255-67. Review. PMID 8807400. Litt M, LaMorticella D, Bond CT, Adelman JP. Gene structure and chromosome mapping of the human small-conductance calcium-activated potassium channel SK1 gene (KCNN1). Cytogenet Cell Genet. 1999;86(1):70-3. PMID 10516439. Pluznick, J. L., Wei, P., Grimm, P. R., & Sansom, S. C. (2005). BK-{beta}1 subunit: immunolocalization in the mammalian connecting tubule and its role in the kaliuretic response to volume expansion. Am J Physiol Renal Physiol 288, F846–F854.  Sah, Pankaj. Ca²⁺ activated K⁺ Currents in Neurones: Types, physiological roles and modulation. Trends Neurosci. 1996. 19, 150-154. Review. Sausbier, M., Hu, H., Arntz, C., Feil, S., Kamm, S., Adelsberger, H., et al. (2004). Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+- activated K+ channel deficiency. Proc Natl Acad Sci U S A 101, 9474– 9478.  Schmalhofer WA, Sanchez M, Dai G, Dewan A, Secades L, Hanner M, Knaus HG, McManus OB, Kohler M, Kaczorowski GJ, Garcia ML. Role of the C-terminus of the high-conductance calcium-activated potassium channel in channel structure and function. Biochemistry. 2005 Aug 2;44(30):10135-44. PMID 16042390.
• Hermann A, Sitdikova GF, Weiger TM. Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels. Biomolecules. 2015 Aug 17;5(3):1870-911. doi: 10.3390/biom5031870. Review. PMID 26287261.
• Kaczorowski GJ, Knaus HG, Leonard RJ, McManus OB, Garcia ML. High-conductance calcium-activated potassium channels; structure, pharmacology, and function. J Bioenerg Biomembr. 1996 Jun;28(3):255-67. Review. PMID 8807400.
• Litt M, LaMorticella D, Bond CT, Adelman JP. Gene structure and chromosome mapping of the human small-conductance calcium-activated potassium channel SK1 gene (KCNN1). Cytogenet Cell Genet. 1999;86(1):70-3. PMID 10516439.
• Schmalhofer WA, Sanchez M, Dai G, Dewan A, Secades L, Hanner M, Knaus HG, McManus OB, Kohler M, Kaczorowski GJ, Garcia ML. Role of the C-terminus of the high-conductance calcium-activated potassium channel in channel structure and function. Biochemistry. 2005 Aug 2;44(30):10135-44. PMID 16042390. Linde8 (talk) 03:09, 13 October 2015 (UTC)

BK Channels are voltage dependent and SK Channels are voltage independent (Just a point I want to touch on). Linde8 (talk) 15:58, 22 October 2015 (UTC)

On the biophysics group I signed up to give feedback for your review paper, but I'm pretty swamped this week so I look next week and if you have some of the body of the review paper posted then I'll be happy to give some comments and see if I can help. Jhenstro (talk) 05:06, 5 November 2015 (UTC)

i signed up to review your paper. It would be great if you could upload your review paper! Rincrate (talk) 03:07, 11 November 2015 (UTC)

The following is a draft of my review article. Portions of this article not covered in the wikipedia page on this topic will be added to the existing encyclopedia article. Thank you for your comments and suggestions.

Calcium activated potassium channels, as the name implies are potassium channels that are activated by calcium. In the family of these channels there are three different subtypes. BK channels which have very high conductance (up to 300 pS), IK channels with intermediate conductance, and SK channels with small conductances(5-20 pS). Though not implied in the name these channels can also be activated by voltage. The different modes of activation in these channels are thought to be independent of one another. This feature of the channel allows them to participate in many different physiologic functions. Like other potassium channels they are involved in hyper polarization of cells after an action potential. The calcium activated property of these channels allows them to participate in vaso-reguation, auditory tuning of hair cells, and also the circadian rhythm. At night, the BK subtype of these changes is expressed in the suprachiasmatic nucleus causing silencing, and then removed during the day causing excitation. BK channels are also expressed in the membranes of mitochondria, Golgi apparatus, and the nucleus. BK channels in the nucleus are thought to regulate gene expression in some hippocampal neurons. Many studies are being executed to study the effects of oxidative stress on BK channels, with results that suggest that the pores of these channels are modulated by oxidation of cysteine residues. BK channels are made up of 3 different subunits, alpha, beta, and gamma. The alpha subunit consists of seven transmembrane regions with a very large intracellular c-terminus. The beta subunit has two transmembrane regions with a large extracellular loop. Recent research suggests that this loop is associated with calcium binding. The gamma subunit consists of one transmembrane region with a large extracellular region on the n-terminal side of the protein. The beta and gamma subunits are what separate Calcium activated potassium channels from the rest of Potassium channels. BK channels activators are being studied as treatments for coronary heart disease ,other vascular dysfunction diseases, and neuronal ischemia. BK channel blockers are being tested at treatments for unstable bladder, bladder overactivity, and certain neurological disorders. Linde8 (talk) 03:57, 13 November 2015 (UTC)

This is a great start, I found it very easy to read and learned a lot. I would say one small thing to do is to give the rage of activation time to the IK channels with intermediate conductance. Another content thing to update would be to give a similar explanation for the IK and SK channels as you did for the BK chhannels. I think the BK channel description was great and it would round it out if you added in some of those characteristics for the IK and SK channels as well. Jhenstro (talk) 20:17, 14 November 2015 (UTC)

I would agree with Jhenstro that it is easy to follow and understand. The flow is good. As as jhenstro said, giving similar descriptions for the IK and Sk channels as you did for the BK channel. Overall good job! Rincrate (talk) 00:48, 18 November 2015 (UTC) Current Article (Edits Made)

Calcium-activated potassium channel

From Wikipedia, the free encyclopedia

Calcium-activated potassium channels are potassium channels gated by calcium, or are structurally or phylogenetically related to calcium gated channels. In humans they are divided into BK channels, IK channels, and SK channels based on their conductance (big, intermediate, and small conductance).

This family of ion channels is, for the most part, activated by intracellular Ca²⁺ and contains 8 members in the human genome. However, some of these channels (the K_Ca4 and K_Ca5 channels) are responsive instead to other intracellular ligands, such as Na⁺, Cl⁻, and pH. Furthermore, multiple members of family are both ligand and voltage activated, further complicating the description of this family. The K_Ca channel α subunits have six or seven transmembrane segments, similar to the K_V channels but occasionally with an additional N-terminal transmembrane helix. The α subunits make homo- and hetero-tetrameric complexes. The calcium binding domain may be contained in the α subunit sequence, as in K_Ca1, or may be through an additional calcium binding protein such as calmodulin.

Contents

 [hide] 

• 1Homology classification
  • 1.1Human K_Ca Channels
    • 1.1.1BK channel
    • 1.1.2SK channel
    • 1.1.3IK channel
    • 1.1.4Other subfamilies
  • 1.2Prokaryotic K_Ca Channels
• 2See also
• 3References
• 4External links

Homology classification[edit source | edit]

Human K_Ca Channels[edit source | edit]

Below is a list of the 8 known human calcium-activated potassium channel grouped according to sequence homology of transmembrane hydrophobic cores:^[1]

BK channel[edit source | edit]

• K_Ca1.1 (BK, Slo1, Maxi-K, KCNMA1)
  • Beta subunits: β1, β2, β3, β4

SK channel[edit source | edit]

• K_Ca2.1 (SK1, KCNN1)
• K_Ca2.2 (SK2, KCNN2)
• K_Ca2.3 (SK3, KCNN3)

IK channel[edit source | edit]

• K_Ca3.1 (IKCa1, SK4, KCNN4)

Other subfamilies[edit source | edit]

• K_Ca4.1 (Slack, Slo2.2, KCNT1)
• K_Ca4.2 (Slick, Slo2.1, KCNT2)
• K_Ca5.1 (Slo3, KCNU1)

Prokaryotic K_Ca Channels[edit source | edit]

A number of prokaryotic K_Ca channels have been described, both structurally and functionally. All are either gated by calcium or other ligands and are homologus to the human K_Ca channels, in particular the K_Ca1.1 gating ring. These structures have served as templates for ligand gating.

Protein	Species	Ligand	Function	Reference	Kch	Escherichia coli	Unknown	Channel	[2][3]
MthK	Methanothermobacter thermautotrophicus	Calcium, Cadmium, Barium, pH	Channel	[4][5][6][7][8]
TrkA/TrkH	Vibrio parahaemolyticus	ATP, ADP	Channel	[9][10]
KtrAB	Bacillus subtilis	ATP, ADP	Transporter	[11]
GsuK	Geobacter sulfurreducens	Calcium, ADP, NAD	Channel	[12]
TM1088	Thermotoga maritima	Unknown	Unknown	[13]

See also[edit source | edit]

• BK channel
• SK channel