Potassium channel Xavier: Difference between revisions

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Xavier Prat-Resina, Michal Harel

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 ===== Why K+ and not Na+ =====
 To stabilize these naked ions, <scene name='Potassium_Channel/Selectivity_side/1'>a number of carbonyl oxygens</scene> (<scene name='Potassium_Channel/Selectivity_side_labels/3'>Labels</scene>) bind the K<sup>+</sup>  ions. The distance between K<sup>+</sup> ion and carbonyl oxygen is at <scene name='Potassium_Channel/Selectivity_side_size/1'>the perfect width</scene> to accommodate K<sup>+</sup> ions but not Na<sup>+</sup>, ions which are too small. If a Na<sup>+</sup> 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<sup>+</sup> ion to enter the channel.
 ===== Knock-on mechanism =====
-There is room within the selectivity filter for <scene name='Potassium_Channel/Selectivity_side_four/1'>four potassium ions</scene>. 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. Compared to the <scene name='Potassium_Channel/High_filter/1'>high-concentration channel</scene> ([[1k4c]]), when exposed to a low concentration of potassium, the channel assumes a <scene name='Potassium_Channel/Low_con/3'>"low concentration" conformation</scene> ([[1k4d]]) which is sealed shut via interactions with water molecules.<ref name="Zhou"/>
+There is room within the selectivity filter for <scene name='Potassium_Channel/Selectivity_side_four/1'>four potassium ions</scene>. 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 (the knock-on mechanism). This helps explain how the potassium channel can have such a rapid turnover rate. Compared to the <scene name='Potassium_Channel/High_filter/1'>high-concentration channel</scene> ([[1k4c]]), when exposed to a low concentration of potassium, the channel assumes a <scene name='Potassium_Channel/Low_con/3'>"low concentration" conformation</scene> ([[1k4d]]) which is sealed shut via interactions with water molecules.<ref name="Zhou"/>
-==== Closing and opening ====
+==== Physical gating: The Voltage Sensor Domain (VSD) ====
+Channel pore opening is dependent on the membrane voltage, a characteristic that is “sensed” by the <scene name='Potassium_Channel/Voltage_sensors_opening/6'>voltage sensor</scene>.
+The voltage sensor is comprised of <scene name='Potassium_Channel/Voltage_helices/3'>six helices</scene>, S0, S1, S2, S3, S4, & S5. Negatively charged sensor residues are either located in the <scene name='Potassium_Channel/Voltage_external/3'>external cluster</scene>, consisting of Glu 183 (in the [[2r9r]] structure) and Glu 226, or in the <scene name='Potassium_Channel/Voltage_internal/4'>internal cluster</scene> consisting of Glu 154, Glu 236, and Asp 259. The external cluster is exposed to solvent while the internal cluster is buried. <scene name='Potassium_Channel/Voltage_phe/2'>Phenylalanine 233</scene> acts as a separator between the two clusters.<ref name="Long"/> The 7 <scene name='Potassium_Channel/Voltage_phe/3'>positively charged residues</scene> of the voltage sensor are located on the S4 helix. Lys 302 and Arg 305 <scene name='Potassium_Channel/Voltage_lower_pos/1'>form hydrogen bonds</scene> with the internal negative cluster while Arginines 287, 290, 293, 296 and 299 are <scene name='Potassium_Channel/Voltage_solvent/1'>exposed to the extracellular solution</scene> (<scene name='Potassium_Channel/Voltage_sensors_arginines_over/2'>Overview</scene>).  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 <scene name='Potassium_Channel/Open/1'>Open</scene> Channel vs. The <scene name='Potassium_Channel/Closed/1'>Closed</scene> ([[1k4c]]) Channel.<ref name="Long"/> Or view the morph of the <scene name='Potassium_Channel/Morph/3'>channel opening and closing</scene> (<scene name='Potassium_Channel/Morph/4'>Cartoon Design</scene>).
 ===== Hydrophobic gating: Dewetting =====
+After the channel is physically closed, there is a short period time during which there is still current (ions being pumped).
+It is not until the waters leave the hydrophobic pocket that ions cannot be stabilized in the hydrophobic part of the pore and therefore not being brought to the selectivity filter.
+This is called hydrophobic gating, meaning that the gating process is not necessarily mechanical but also chemical.
-===== Physical gating: The Voltage Sensor Domain (VSD) =====
-&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; It is instructive to follow the path of a potassium ion as it enters the cell through the <scene name='Potassium_Channel/Potassium_out/3'>potassium channel</scene>. Upon <scene name='Potassium_Channel/Into_pore/4'>entering the channel</scene>, the K<sup>+</sup> ion first comes into contact with the <scene name='Potassium_Channel/From_extra/4'>selectivity filter</scene>.  The solved structure of the potassium channel by MacKinnon et al. revealed where the channels remarkable selectivity comes from. When entering the <scene name='Potassium_Channel/From_extra/3'>selectivity filter</scene>, K<sup>+</sup> ions are first dehydrated, shedding up to 8 waters. To stabilize these naked ions, <scene name='Potassium_Channel/Selectivity_side/1'>a number of carbonyl oxygens</scene> (<scene name='Potassium_Channel/Selectivity_side_labels/3'>Labels</scene>) bind the K<sup>+</sup>  ions. The distance between K<sup>+</sup> ion and carbonyl oxygen is at <scene name='Potassium_Channel/Selectivity_side_size/1'>the perfect width</scene> to accommodate K<sup>+</sup> ions but not Na<sup>+</sup>, ions which are too small. If a Na<sup>+</sup> 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<sup>+</sup> ion to enter the channel. There is room within the selectivity filter for <scene name='Potassium_Channel/Selectivity_side_four/1'>four potassium ions</scene>. 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.<ref name="Doyle"/> Also, the <scene name='Potassium_Channel/Selectivity_side_polarity/2'>natural polarity of the helices</scene>, with the <scene name='Potassium_Channel/Selectivity_side_polarity/3'>carbonyl oxygens pointing down the pore</scene>, helps pull the positively charged ions through the channel quickly. Compared to the <scene name='Potassium_Channel/High_filter/1'>high-concentration channel</scene> ([[1k4c]]), when exposed to a low concentration of potassium, the channel assumes a <scene name='Potassium_Channel/Low_con/3'>"low concentration" conformation</scene> ([[1k4d]]) which is sealed shut via interactions with water molecules.<ref name="Zhou"/>
-&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; The <scene name='Potassium_Channel/High_filter_broad/1'>selectivity filter</scene> only makes up the beginning of the <scene name='Potassium_Channel/Full_pore/5'>channel pore</scene>. With the exception of the selectivity filter, the pore lining is <scene name='Potassium_Channel/Full_pore_hdryo/2'>mainly hydrophobic</scene>. This hydrophobic lining provides an inert surface over which the diffusing ion can slide unimpaired.  Immediately following the selectivity filter is an <scene name='Potassium_Channel/Full_pore_h20/1'>aqueous cavity</scene> (<scene name='Potassium_Channel/Full_pore_h20_spin/1'>Spinning Model</scene>). K<sup>+</sup> 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 <scene name='Potassium_Channel/High_filter_aromatic/2'>aromatic residues</scene> which help form a seal between the pore and the intracellular cytoplasm.<ref name="Doyle"/>
-====Voltage Sensor====
-&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Channel pore opening is dependent on the membrane voltage, a characteristic that is “sensed” by the <scene name='Potassium_Channel/Voltage_sensors_opening/6'>voltage sensor</scene>. The voltage sensor is comprised of <scene name='Potassium_Channel/Voltage_helices/3'>six helices</scene>, S0, S1, S2, S3, S4, & S5. Negatively charged sensor residues are either located in the <scene name='Potassium_Channel/Voltage_external/3'>external cluster</scene>, consisting of Glu 183 (in the [[2r9r]] structure) and Glu 226, or in the <scene name='Potassium_Channel/Voltage_internal/4'>internal cluster</scene> consisting of Glu 154, Glu 236, and Asp 259. The external cluster is exposed to solvent while the internal cluster is buried. <scene name='Potassium_Channel/Voltage_phe/2'>Phenylalanine 233</scene> acts as a separator between the two clusters.<ref name="Long"/> The 7 <scene name='Potassium_Channel/Voltage_phe/3'>positively charged residues</scene> of the voltage sensor are located on the S4 helix. Lys 302 and Arg 305 <scene name='Potassium_Channel/Voltage_lower_pos/1'>form hydrogen bonds</scene> with the internal negative cluster while Arginines 287, 290, 293, 296 and 299 are <scene name='Potassium_Channel/Voltage_solvent/1'>exposed to the extracellular solution</scene> (<scene name='Potassium_Channel/Voltage_sensors_arginines_over/2'>Overview</scene>).  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 <scene name='Potassium_Channel/Open/1'>Open</scene> Channel vs. The <scene name='Potassium_Channel/Closed/1'>Closed</scene> ([[1k4c]]) Channel.<ref name="Long"/> Or view the morph of the <scene name='Potassium_Channel/Morph/3'>channel opening and closing</scene> (<scene name='Potassium_Channel/Morph/4'>Cartoon Design</scene>).
-&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 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 [[Pharmaceutical drugs|therapeutic intervention]] into Potassium channel related diseases.
 </StructureSection>
+==3D structures of potassium channel==
+[[Potassium channel]]
 == References ==
 <references/>