Ion Channels regulate the function of excitable and non-excitable cells. A large super-family of genes encode these proteins. Additional diversity is generated by alternative splicing, RNA editing, protein-assembly as homo- or hetero-multimers, post-translational modifications, co-assembly with other proteins in signalosomes and by varied sub-cellular localization.|~|/files/powerpoints_images/node343610/Slide2.JPG|~|563|~|422|~|0
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Ion Channels regulate the function of excitable and non-excitable cel...
The IUPHAR Database lists 194 genes that encode voltage-gated and ligand-gated ion channels. The URL for this site is: http://www.iuphar-db.org/DATABASE/ReceptorFamiliesForward?type=IC.|~|/files/powerpoints_images/node343610/Slide4.JPG|~|563|~|422|~|0
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The IUPHAR Database lists 194 genes that encode voltage-gated and lig...
I will focus on the channels included in the red box.|~|/files/powerpoints_images/node343610/Slide9.JPG|~|563|~|422|~|0
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I will focus on the channels included in the red box.
To examine the ancient divisions of the voltage-sensitive ion channel multigene superfamily (including K, Na, Ca, and cNMP channels), we analyzed the S4 segments. The tree presented in figure shows three monophyletic groups, one consisting of the potassium channels, another of the sodium and calcium channels, and the third including the two cyclic nucleotide-gated channels; within the Na /Ca group, the Na channels and Ca channels each cluster into their own groups.|~|/files/powerpoints_images/node343610/Slide10.JPG|~|563|~|422|~|0
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To examine the ancient divisions of the voltage-sensitive ion channel...
The simplest are the inward rectifier potassium channels that are tetramers of proteins, each of which are comprised of two transmembrane segments and one pore segment. The 2-pore potassium channels contain four transmembrane segments and two pore segments. The functional channels are dimers. The K2P channels may have arisen by a duplication from an ancient two-TM ancestral gene. The voltage-gated potassium channels, the calcium-activated potassium channels, the cyclic nucleotide-gated channels and TRP channels are tetramers of proteins, each of which contain six transmembrane segments and one pore segment. These 6TM channels may have arisen as a fusion of a 2TM channel and a 4TM protein. Interestingly, a 4TM voltage-sensitive phosphatase has been discovered.|~|/files/powerpoints_images/node343610/Slide11.JPG|~|563|~|422|~|0
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The simplest are the inward rectifier potassium channels that are tet...
In the crystal structure of the 6TM Kv1.2 channel by Roderick MacKinnon\'s group, the pore is formed by the S5-P region-S6 segments of each of the four subunits in the tetramer. This region is similar to the pore region in KcsA from bacteria and the inward rectifier potassium channels. The other distinct part of this channel is comprised of the S1-S4 transmembrane segments; the voltage sensor is contained within this region. Proteins that are similar to this region include Ci-VSP, a voltage-activated phosphatase from Ciona intestinalis and the Hv1 proton channel. Thus, one could imagine a fusion of an ancient protein similar to Ci-VSP and another ancient protein similar to KcsA, resulting in a 6TM voltage-gated potassium channel. |~|/files/powerpoints_images/node343610/Slide12.JPG|~|563|~|422|~|0
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In the crystal structure of the 6TM Kv1.2 channel by Roderick MacKinn...
Voltage-gated sodium and voltage-gated calcium channels are each comprised of a single protein with four domains, each domain containing six transmembrane segments and one pore segment (i.e. each domain is equivalent to a voltage-gated potassium channel subunit).|~|/files/powerpoints_images/node343610/Slide13.JPG|~|563|~|422|~|0
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Voltage-gated sodium and voltage-gated calcium channels are each comp...
While the cyclic nucleotide and voltage-gated potassium channel genes each encode a single domain that contains the Sl-S6 segments, the voltage-gated sodium and calcium channel genes have four such domains repeated in tandem. To examine the relationship between these four domains, alignments of their amino acid sequences were analyzed by using PAUP protein parsimony (heuristic search). The unrooted topology shown in figure places domains I and III, on the one hand, and domains II and IV, on the other hand, into monophyletic groups.|~|/files/powerpoints_images/node343610/Slide14.JPG|~|563|~|422|~|0
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While the cyclic nucleotide and voltage-gated potassium channel genes...
On the basis of electrophysiological data and the sequence similarities of each domain of the sodium channel to the corresponding domain of the calcium channel, Hille (1989) hypothesized that a common ancestral single-domain channel gene gave rise to the primordial calcium channel by two intragenic duplications and then gave rise to the sodium channel by further divergence following gene duplication. The tree presented in figure supports this scheme. As diagrammed in the figure, a primordial single-domain gene underwent an internal duplication to create a two-domain structure; following sequence divergence of the two domains, a second internal duplication gave rise to the four domain structure known today. Hence, domains I and III, as well as domains II and IV, remain more similar to each other as a result of their evolutionary history, and these relationships are reflected in the topology of the tree in the figure. One implication of this scheme is that an ancestral two-domain peptide was capable of producing a functional channel protein, since it existed long enough both for substantial sequence divergence to occur and to give rise to the four-domain structure by an additional duplication.|~|/files/powerpoints_images/node343610/Slide15.JPG|~|563|~|422|~|0
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On the basis of electrophysiological data and the sequence similariti...
Synteny describes the physical co-localization of genetic loci on the same chromosome within an individual or species. Shared synteny describes preserved co-localization of genes on chromosomes of different species. During evolution, rearrangements to the genome such as chromosome translocations may separate two loci apart, resulting in the loss of synteny between them. In the slide above, the cluster of Kv1 sub-family genes on human chromosome 1p13 is syntenic to the cluster of homologous genes on rat chromosome 2q34. Other examples of shared synteny are shown above.|~|/files/powerpoints_images/node343610/Slide17.JPG|~|563|~|422|~|0
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Synteny describes the physical co-localization of genetic loci on the...
Proteins within a potassium channel-sub-family can coassemble with each other, but not with members of other sub-families. The tetramerization domain resides in the N-terminus of these proteins. In the Kv-sub-family, Kv5. Kv6, Kv8 and Kv9 sub-family proteins can coassemble and modify proteins belonging to the Kv2 sub-family of proteins. |~|/files/powerpoints_images/node343610/Slide20.JPG|~|563|~|422|~|0
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Proteins within a potassium channel-sub-family can coassemble with ea...
Different mutations in the Cav1.1 gene can cause different diseases e.g. malignant hyperthermia, muscular dysgenesis and hypokalemic periodic paralysis i.e. different mutations in a single gene can result in different diseases. In contrast, mutations in Cav1.1 and Nav1.4 can both lead to hypokalemic periodic paralysis i.e. mutations in different genes can cause a single type of disease. |~|/files/powerpoints_images/node343610/Slide21.JPG|~|563|~|422|~|0
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Different mutations in the Cav1.1 gene can cause different diseases e...
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