Potassium Channel

spinqualitylabelsall models Structure of the Potassium Channel complex with K+ ions, (2r9r) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D       Potassium Channels control cell membrane electric potentials by selectively allowing diffusion of K+ across the membrane. K+ Channels extend across the cell membrane, a 40Å thick lipid bilayer which ions cannot cross. Potassium homeostasis is crucial for nearly all living cells, but is particularly important for the correct function of neurons. Neurons produce electrical impulses known as action potentials, allow for cellular communication processes like neurotransmitter release or to initiate intercellular processes muscle contraction. At the onset of an action potential, sodium ions flood across the plasma membrane of neurons via sodium channels. The change in polarity of the plasma membrane caused by the sodium ion influx inactivates sodium channels. Potassium channels subsequently open allowing the selective diffusion of K+ ions across the plasma membrane, returning the membrane polarity to neutral. After the action potential has passed, channels recreate the high potassium concentration within the cell in preparation for the next stiumulus. Mutations in voltage-gated potassium channel KCNC3 have been linked with neurodevelopmental disorders and neurodegeneration.       Potassium channels possess two traits that are seemingly mutually exclusive. Firstly, potassium channels have exquisite selectivity, with an amazing 10,000 fold selectivity for K+ ions over sodium ions. Considering the only difference by which potassium ions can be differentiated from sodium ions is potassium ions’ 1.33Å Pauling radius vs. Sodium’s .95Å radius, the selectivity of potassium channels is remarkable. Second, despite its remarkable selectivity, potassium channels allow for the transfer of K+ ions across the cell membrane at a rate of nearly 108 per second, nearly at the diffusion rate limit. Potassium channels are able to achieve these remarkable feats due to its amazing structural architecture, which contains several features which not only can sense the voltage potential across a membrane, but also selectively ferry K+ ions without any outside energy expenditure.       The overall structure of the voltage gated potassium channel can be seen in the image at the left. It is comprised of 4 identical subunits and contains several key features which will be analyzed. Primarily, a transmembrane region marked between the parallel lines in the figure. This region houses the channel pore, composed of interwoven helices in a teepee conformation, the all-important “selectivity filter”, providing the channel with its remarkable 10,00 fold selectivity for K+ ions over Na+ ions and the “voltage sensor” which is uses well placed arginine and acidic residues to determine the membrane polarity and open/close the channel in response. Selectivity Filter and Pore       It is instructive to follow the path of a potassium ion as it enters the cell through the potassium channel. Upon entering the channel, the K+ ion first comes into contact with the selectivity filter. The solved structure of the potassium channel by MacKinnon et al. revealed where the channels remarkable selectivity comes from. When entering the selectivity filter, K+ ions are first dehydrated, shedding up to 8 waters. To stabilize these naked ions, a number of carbonyl oxygens (Labels) bind the K+ ions. The distance between K+ ion and carbonyl oxygen is at the perfect width to accommodate K+ ions but not Na+, ions which are too small. If a Na+ ion were to lose its water shell, the carbonyl oxygens could not successfully stabilize it in its naked form and thus it is energetically unfavorable for a Na+ ion to enter the channel. There is room within the selectivity filter for four potassium ions. This, as it turns out, is crucial as the presence of the positive cations in close proximity to one another effectively pushes the potassium ions through the filter via electrostatic forces. This helps explain how the potassium channel can have such a rapid turnover rate. Also, the natural polarity of the helices, with the carbonyl oxygens pointing down the pore, helps pull the positively charged ions through the channel quickly. Compared to the high-concentration channel (1k4c), when exposed to a low concentration of potassium, the channel assumes a "low concentration" conformation (1k4d) which is sealed shut via interactions with water molecules.       The selectivity filter only makes up the beginning of the channel pore. With the exception of the selectivity filter, the pore lining is mainly hydrophobic. This hydrophobic lining provides an inert surface over which the diffusing ion can slide unimpaired. Immediately following the selectivity filter is an aqueous cavity (Spinning Model). K+ ions, after passing through the filter, rehydrate in this cavity, helping overcome much of the energetic difficulty of having a positively charged cation within a hydrophobic membrane. At the bottom of the 34Å pore containing transmembrane region lies a number of aromatic residues which help form a seal between the pore and the intracellular cytoplasm. Voltage Sensor       Channel pore opening is dependent on the membrane voltage, a characteristic that is “sensed” by the voltage sensor. The voltage sensor is comprised of six helices, S0, S1, S2, S3, S4, & S5. Negatively charged sensor residues are either located in the external cluster, consisting of Glu 183 (in the 2r9r structure) and Glu 226, or in the internal cluster consisting of Glu 154, Glu 236, and Asp 259. The external cluster is exposed to solvent while the internal cluster is buried. Phenylalanine 233 acts as a separator between the two clusters. The 7 positively charged residues of the voltage sensor are located on the S4 helix. Lys 302 and Arg 305 form hydrogen bonds with the internal negative cluster while Arginines 287, 290, 293, 296 and 299 are exposed to the extracellular solution (Overview). When the voltage sensor is exposed to a strong negative electric field in the intracellular membrane, the positive gating charges shift inward with the α-carbon of Arg 290 coming in close proximity to Phe 233. This shift effectively squeezes the pore shut, closing the intracellular-extracellular pathway. For a comparison see: The Open Channel vs. The Closed (1k4c) Channel. Or view the morph of the channel opening and closing (Cartoon Design).       Overall, Potassium channels are remarkable structures that allow for near diffusion limit transfer of molecules with sub-angstrom specificity. Our understanding of the structure of Potassium Channels has opened up the potential for therapeutic intervention into Potassium channel related diseases.

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This article was developed based on lectures given in Chemistry 543 by Prof. Clarence E. Schutt at Princeton University.

Potassium channels (KCh) are subdivided into voltage-gated KCh and calcium-dependent KCh. The latter are subdivided into high- (BK, LKCa), intermediate- and small-conductance KCh (human SK1, rat SK2, SKCa). The T1 domain is a highly conserved N-terminal domain which is responsible for driving the tetramerization of the KCh α subunit. The inward rectifier KCh (IRK) passes current more easily in the inward direction. MthK is a calcium-dependent KCh from Methanobacterium thermoautrophicum.

3D structures of Potassium Channels

Updated on 10-April-2014

neurodevelopmental disorders, 1k4c, 1k4d, 2r9r, 1k4c, therapeutic intervention, 2wlo - MmKCh - Magnetospirillum magnetoacticum
2k44 – KCh voltage-sensor paddle domain – NMR
3e86, 3e83 – BcKCh transmembrane domain – Bacillus cereus
3e8g, 3e89, 3e8b, 3e8f, 3e8h – BcKCh transmembrane domain +ions
2q67, 2q68, 2q69, 2q6a, 3ouf – BcKCh (mutant)
2ahy, 2ahz – BcKCh+ions
1bl8, 1f6g - SlKCh (mutant) - Streptomyces lividans
2qto - SlKCh
1j95 - SlKCh+K+tetrabutylammonium
1jvm - SlKCh (mutant)+Rb+tetrabutylammonium
1jq1, 1jq2 - SlKCh inner transmembrane segment - NMR
3ifx - SlKCh pore domain
3pjs – SlKCh + antibody
2pnv – rKCh leucine zipper domain SKCa – rat
3lut - rKCh Kv1.2 (mutant)
1dsx - rKCh N-terminal (mutant)
1qdv, 1qdw - rKCh Kv1.2 N-terminal
1kn7 - rKCh Kv1.4 N-terminal (mutant) - NMR
1nn7 - rKCh Kv4.2 N-terminal T1 domain
3eau - rKCh β-2 +cortisone
3eb3, 3eb4 - rKCh β-2 (mutant) + cortisone
4hoi – mKCh Kv10.1 PAS domain – mouse
1a68, 1eod, 1eoe, 1eof, 3kvt - AcKCh Kv1.1 T1 domain (mutant) - Aplysia californica
1t1d - AcKCh Kv1.1 T1 domain
1b4g, 1b4i - hKCh inactivation domain - human - NMR
1byw - hKCh ERG N-terminal (mutant)
1ujl - hKCh ERG1 extracellular linker - NMR
2l1m, 2l4r, 2l0w - hKCh HERG - NMR
1s1g - hKCh Kv4.3 T1 domain
2ovc - hKCh Kv7.4 T1 domain
3bj4 - hKCh Kv7.1 C-termianl
3hfc, 3hfe - hKCh Kv7.1 (mutant)
4bw5 – hKCh TREK-2
1zsx - hKCh β-2
1ztn – hKCH RAW3 inactivation gate – NMR
1zto - hKCH RCK4 inactivation gate – NMR
3co2, 1vp6 - MlotiK1 cyclic nucleotide binding domain - Mesorhizobium loti
1ho2, 1ho7 - KCh L45 segment - Drosophila melanogaster - NMR
2kyh - AeKCh voltage ensing domain - Aeropyrum pernix - NMR
2wll - KCh KIRBAC1.1 - Burkholderia pseudomalie
1bei - KCh Kv1.3 – Stichodactyla helianthus

Potassium channel complex with protein

2nz0 – hKCh Kv4.3 N-terminal+KV channel interacting protein 1
2i2r - rKCh Kv4.3 N-terminal+KV channel interacting protein 1
1s6c - rKCh Kv4.2 N-terminal+KV channel interacting protein 1
2a79, 1qrq - rKCh Kv1.2 + beta2
4jta, 4jtc, 4jtd - rKCh Kv1.2-2.1 + KCh toxin
2r9r - rKCh
1qx7 – rKCh SKCa+ calmodulin
1g4y – rKCh rSK2 calmodulin binding domain SKCa + calmodulin
1exb - rKCh Kv1.1 T1 domain + KV beta2 protein
2p7t - rKCh + FAV
3lnm - rKCh Kv2.1/KCh Kv1.2 (mutant)
3eff - mKCh + FAB
2w0f - mKCh + FAB + tetraoctylammonium
2hg5, 2h8p, 2hfe - KCh + mFAB
3f7v, 3f7y, 3fb5, 3fb7, 3fb8, 3gb7, 3hpl, 3iga, 3or6, 3or7, 1r3i, 1r3j, 1r3k,1r3l, 1s5h, 2atk, 2bob, 2boc, 2dwd, 2dwe, 2hvj, 2hvk, 2ih1, 2ih3, 2itc, 2itd, 2jk5, 2nlj - mKCh (mutant) + FAB
3f5w, 1zwi, 2hjf - mKCh (mutant) + antibody heavy+light chains
1k4c, 1k4d - SlKCh (mutant) + antibody heavy+light chains
2a0l - AeKCh + FV
1orq - AeKCh (mutant) + FAB
2a9h - SlKCh (mutant) + charybdotoxin

Inward rectifier KCh

1u4f,3agw - mIRK 2 cytoplasmic domain
2xky - mIRK 2 cytoplasmic domain - EM
2gix, 3vsq - mIRK 2 cytoplasmic domain (mutant)
2e4f - mIRK 2 fragment
1n9p, 1u4e - mIRK 1 cytoplasmic domain
3k6n - mIRK 1 cytoplasmic domain (mutant)
3at8, 3at9, 3ata, 3atb, 3atd, 3ate, 3atf, 3auw, 3syo - mIRK 3.2
3syc, 3syp - mIRK 3.2 (mutant)
3sya - mIRK 3.2 + PIP2
3syq - mIRK 3.2 (mutant) + PIP2
4kfm - mIRK 3.2 + guanine nucleotide-biding protein
1xl4, 1xl6, 2wlk, 2x6a, 2x6b, 2x6c - MmIRK KIRBAC3.1
4lp8 - MmIRK KIRBAC3.1 (mutant)
1p7b - BpIRK C-terminal
3spc – cIRK 2.2 + DGPP – chicken
3spg, 3sph – cIRK 2.2 (mutant) + PIP2
3spi – cIRK 2.2 + PIP2
3spj – cIRK 2.2 (mutant)
3ukm – hIRK TWIK-1
3um7 – hIRK TRAAK
3zrs – MmIRK 10

MthK

2ogu, 2fy8, 2aej, 2aem, 1lnq - MthK RCK domain - Methanobacterium thermoautrophicum
3ldc, 3ldd, 3lde, 3ous – MthK residues 28-99 (mutant)
2aef, 3kxd, 4ei2, 4l73, 4l74, 4l75, 4l76 - MthK RCK domain + Ca
3rbx, 3rbz - MthK RCK domain (mutant) + Ca
3r65, 4hyo, 4hz3 – MthK pore domain (mutant)

Large conductance calcium-activated KCh

3mt5 - hBK cytoplasmic domain
1jo6 - BK beta 2 N-terminal KCNMB2 encoded LKCa - NMR
3u6n – BK – Danio rerio

Potassium/Sodium channel

3k03, 3k04, 3k06, 3k08, 3k0d, 3k0g – BcNaK
3t1c, 3t2m, 3t4d, 3t4z, 3tcu, 3tet – BcNaK (mutant)

Calcium-activated KCh

3naf – hKCh α1 subunit

Small conductance calcium-activated KCh

1kkd – rKCh calmodulin-binding domain - NMR - rat
3sjq, 4g27, 4g28, 4j9y, 4j9z - rKCh calmodulin-binding domain + calmodulin
2pnv – rKCh leucine zipper domain SKCa

Additional Resources

For Additional Information, See: Membrane Channels & Pumps

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David Canner, Alexander Berchansky, Ann Taylor, Michal Harel, Joel L. Sussman