A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.

West, James W.; Patton, D E; Scheuer, Todd; Wang, Y; Goldin, Alan L.; Catterall, William A.

doi:10.1073/pnas.89.22.10910

Cited by 747 publications

(708 citation statements)

References 29 publications

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“…Therefore, it is possible that these mutant channels might increase the energy requirement from the closed states to the inactivated state (27). After replacement of phenylalanine by methionine to create mutant F1342M, we observed a very small effect on inactivation, which is in accordance with results from previous studies on the Na ϩ channel (28). At this point, however, we cannot confirm that just one critical amino acid is linked to the impaired inactivation in the IVS5 region and is responsible for channel gating.…”

Section: Discussionsupporting

confidence: 82%

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

Bódi¹,

Koch²,

Yamaguchi³

et al. 2002

Journal of Biological Chemistry

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The role of inactivated channel conformation and use dependence for diltiazem, a specific benzothiazepine calcium channel inhibitor, was studied in chimeric constructs and point mutants created in the IVS5 transmembrane segment of the L-type cardiac calcium channel. All mutations, chimeric or point mutations, were restricted to IVS5, while the YAI-containing segment in IVS6, i.e. the primary interaction site with benzothiazepines, remained intact. Slowed inactivation rate and incomplete steady state inactivation, a behavior of some mutants, were accompanied by a reduced or by a complete loss of use-dependent block by diltiazem. L-type Ca 2ϩ channels of cardiac, skeletal, and smooth muscle play a central role in excitation-contraction coupling. It is also believed that these channels may participate in the pathophysiology of some cardiac arrhythmias, hypertension, and angina pectoris (1-4). Increases in [Ca 2ϩ ] i have been linked to a variety of changes in membrane properties that contribute to the changes in excitability, conduction, refractoriness, automaticity, and vascular resistance (1-4). In terms of excitation-contraction coupling, Ca 2ϩ enters the cell during depolarization through voltage-activated calcium channels and triggers contraction but also is responsible for activation of other cellular functions. In the course of sustained depolarization, Ca 2ϩ currents progressively undergo voltage-dependent inactivation with specific kinetics, primarily regulated by the membrane potential.Ca 2ϩ channels are the target for three main classes of drugs that include dihydropyridines (DHP), 1 phenylalkylamines (PAA), and benzothiazepines (BTZ). These molecules bind specifically to different sites of the Ca 2ϩ channel ␣ 1 subunit, and their binding domains are allosterically linked to each other (5-7). Ca 2ϩ channel antagonists, particularly diltiazem and verapamil, block calcium channels in a voltage-and use-dependent manner; thus the binding of the drug facilitates protein conformational changes that alter channel function by interfering with channel gating. These drugs serve as useful tools in dissecting molecular mechanisms of channel inactivation. Several amino acid residues that are involved in Ca 2ϩ antagonist binding, when mutated, change the electrophysiological properties of the channel, such as voltage-dependent inactivation. Single amino acids in segments IIIS6 and IVS6 (5, 8 -11) have been identified as determinants of inactivation. Mutation of key amino acids in these segments alters not only the high affinity drug-binding sites but also the complexity of the kinetic behavior of the channels, consequently changing use-dependent block particularly for the PAAs and BTZs (for review, see Ref. 12).Our previous finding showed that a segment in IVS5 of the human ␣ 1C (Ca v 1.2) subunit is critically involved in inactivation of the channel (13). Consequently, mutants constructed in this region lost the characteristic use-dependent block by PAA and BTZ and recovered from inactivation significantly faster a...

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Section: Discussionsupporting

confidence: 82%

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

Bódi¹,

Koch²,

Yamaguchi³

et al. 2002

Journal of Biological Chemistry

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“…In this regard the hydrophobic patch that we identified in the M4-M5 loop of ICMT may be involved. Perhaps in a similar manner to the hydrophobic patch in sodium channels (42), the cytosolic M4-M5 loop of ICMT is capable of hinging toward the lipid membrane. Further investigation will be important to determine the specifics of substrate binding and any associated structural changes in ICMT.…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of the Integral Membrane Methyltransferase Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Reveals Potential Substrate Binding Sites

Diver

Long

2014

Journal of Biological Chemistry

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Background: Isoprenylcysteine carboxyl methyltransferase (ICMT) is an integral membrane enzyme that modifies CAAX proteins. Results: Mutational analysis has identified residues important for activity and substrate recognition. Conclusion: Crucial residues are found in cytosolic and membrane-embedded regions, consistent with the ability of ICMT to bind both water-soluble and lipophilic substrates. Significance: Insights into the enzymatic mechanism of ICMT may assist with inhibitor development.

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“…These positive charges in the S4 segments serve as gating charges and move across the membrane electric field in response to changes in membrane potential, initiating conformational changes that open and close the pore (6, 7). The cytoplasmic linker connecting domains III and IV forms the fast inactivation gate, which folds in and blocks the pore during fast inactivation (2,(8)(9)(10).…”

mentioning

confidence: 99%

Mapping the receptor site for α-scorpion toxins on a Na ⁺ channel voltage sensor

Wang

Yarov‐Yarovoy

Kahn

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

124

121

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Fig. 2. (A)Interaction web of top-down and bottom-up effects in the eelgrass study system. The top predator is the sea otter (E. lutris), the mesopredators are crabs (Cancer spp. and Pugettia producta), the epiphyte mesograzers are primarily an isopod (I. resecata) and a sea slug (P. taylori), and algal epiphyte competitors of eelgrass primarily consist of chain-forming diatoms, and the red alga Smithora naiadum. Solid arrows indicate direct effects, dashed arrows indicate indirect effects, and the plus and minus symbols indicate positive and/or negative effects on trophic guilds and eelgrass condition. C, competitive interaction; T, trophic interaction. (Original artwork by A. C. Hughes.) (B-E) Survey results testing for the effects of sea otter density on eelgrass bed community properties (Tables S2 and S3). Elkhorn Slough (sea otters present and high nutrients) eelgrass beds (n = 4) are coded in red, and the Tomales Bay reference site (no sea otters, low nutrients) beds (n = 4) are coded in blue. (B) Crab biomass and size structure of two species of Cancer crabs; (C) grazer biomass per shoot and large grazer density; (D) algal epiphyte loading; and (E) aboveground and belowground eelgrass biomass. DW, dry weight; FW, fresh weight.

show abstract

A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.

Abstract: The inward Na+ current underlying the action potential in nerve is terminated by inactivation. The

Cited by 747 publications

References 29 publications

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

Mutational Analysis of the Integral Membrane Methyltransferase Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Reveals Potential Substrate Binding Sites

Mapping the receptor site for α-scorpion toxins on a Na ⁺ channel voltage sensor

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A cluster of hydrophobic amino acid residues required for fast Na(+)-channel inactivation.

Abstract: The inward Na+ current underlying the action potential in nerve is terminated by inactivation. The

Cited by 747 publications

References 29 publications

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

The Role of Region IVS5 of the Human Cardiac Calcium Channel in Establishing Inactivated Channel Conformation

Mutational Analysis of the Integral Membrane Methyltransferase Isoprenylcysteine Carboxyl Methyltransferase (ICMT) Reveals Potential Substrate Binding Sites

Mapping the receptor site for α-scorpion toxins on a Na + channel voltage sensor

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Mapping the receptor site for α-scorpion toxins on a Na ⁺ channel voltage sensor