Point mutations at the local anesthetic receptor site modulate the state-dependent block of rat Nav1.4 sodium channels by pyrazoline-type insecticides

2007 ◽  
Vol 28 (3) ◽  
pp. 655-663 ◽  
Author(s):  
Kristopher S. Silver ◽  
David M. Soderlund
Keyword(s):  
Sodium Channels ◽  
Local Anesthetic ◽  
Point Mutations ◽  
Receptor Site ◽  
The State ◽  
State Dependent

Inhibition of Nav1.7 and Nav1.4 Sodium Channels by Trifluoperazine Involves the Local Anesthetic Receptor

2006 ◽  
Vol 96 (4) ◽  
pp. 1848-1859 ◽  
Author(s):  
Patrick L. Sheets ◽  
Peter Gerner ◽  
Chi-Fei Wang ◽  
Sho-Ya Wang ◽  
Ging Kuo Wang ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Local Anesthetic ◽  
Receptor Site ◽  
Inhibitory Peptide ◽  
Sensory Blockade ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Steady State Inactivation ◽  
Channel Interactions

The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Nav1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 μM TFP induce major decreases in Nav1.7 and Nav1.4 current amplitudes and that 2 μM TFP causes hyperpolarizing shifts in the steady-state inactivation of Nav1.7 and Nav1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Nav1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.

scholarly journals Atomic determinants of state-dependent block of sodium channels by charged local anesthetics and benzocaine

FEBS Letters ◽  
2006 ◽  
Vol 580 (26) ◽  
pp. 6027-6032 ◽  
Author(s):  
Denis B. Tikhonov ◽  
Iva Bruhova ◽  
Boris S. Zhorov
Keyword(s):  
Sodium Channels ◽  
Local Anesthetics ◽  
State Dependent

scholarly journals On Uncertainty Relations and Entanglement Detection with Mutually Unbiased Measurements

2015 ◽  
Vol 22 (01) ◽  
pp. 1550005 ◽  
Author(s):  
Alexey E. Rastegin
Keyword(s):  
The State ◽  
Uncertainty Relations ◽  
Trade Off ◽  
Entropic Uncertainty Relations ◽  
Finite Dimensional ◽  
State Dependent ◽  
Entanglement Detection

We formulate some properties of a set of several mutually unbiased measurements. These properties are used for deriving entropic uncertainty relations. Applications of mutually unbiased measurements in entanglement detection are also revisited. First, we estimate from above the sum of the indices of coincidence for several mutually unbiased measurements. Further, we derive entropic uncertainty relations in terms of the Rényi and Tsallis entropies. Both the state-dependent and state-independent formulations are obtained. Using the two sets of local mutually unbiased measurements, a method of entanglement detection in bipartite finite-dimensional systems may be realized. A certain trade-off between a sensitivity of the scheme and its experimental complexity is discussed.

Block of Human Heart hH1 Sodium Channels by the Enantiomers of Bupivacaine

2000 ◽  
Vol 93 (4) ◽  
pp. 1022-1033 ◽  
Author(s):  
Carla Nau ◽  
Sho-Ya Wang ◽  
Gary R. Strichartz ◽  
Ging Kuo Wang
Keyword(s):  
Human Heart ◽  
Point Mutations ◽  
Cell Voltage ◽  
Site Directed Mutagenesis ◽  
Na Channel ◽  
Amino Acid Residues ◽  
Na Channels ◽  
State Dependent ◽  
Positively Charged

Background S(-)-bupivacaine reportedly exhibits lower cardiotoxicity but similar local anesthetic potency compared with R(+)-bupivacaine. The bupivacaine binding site in human heart (hH1) Na+ channels has not been studied to date. The authors investigated the interaction of bupivacaine enantiomers with hH1 Na+ channels, assessed the contribution of putatively relevant residues to binding, and compared the intrinsic affinities to another isoform, the rat skeletal muscle (mu1) Na+ channel. Methods Human heart and mu1 Na+ channel alpha subunits were transiently expressed in HEK293t cells and investigated during whole cell voltage-clamp conditions. Using site-directed mutagenesis, the authors created point mutations at positions hH1-F1760, hH1-N1765, hH1-Y1767, and hH1-N406 by introducing the positively charged lysine (K) or the negatively charged aspartic acid (D) and studied their influence on state-dependent block by bupivacaine enantiomers. Results Inactivated hH1 Na+ channels displayed a weak stereoselectivity with a stereopotency ratio (+/-) of 1.5. In mutations hH1-F1760K and hH1-N1765K, bupivacaine affinity of inactivated channels was reduced by approximately 20- to 40-fold, in mutation hH1-N406K by approximately sevenfold, and in mutations hH1-Y1767K and hH1-Y1767D by approximately twofold to threefold. Changes in recovery of inactivated mutant channels from block paralleled those of inactivated channel affinity. Inactivated hH1 Na+ channels exhibited a slightly higher intrinsic affinity than mu1 Na+ channels. Conclusions Differences in bupivacaine stereoselectivity and intrinsic affinity between hH1 and mu1 Na+ channels are small and most likely of minor clinical relevance. Amino acid residues in positions hH1-F1760, hH1-N1765, and hH1-N406 may contribute to binding of bupivacaine enantiomers in hH1 Na+ channels, whereas the role of hH1-Y1767 remains unclear.

Differential Interaction ofR-Mexiletine with the Local Anesthetic Receptor Site on Brain and Heart Sodium Channel α-Subunits

1999 ◽  
Vol 56 (6) ◽  
pp. 1238-1244 ◽  
Author(s):  
Thomas Weiser ◽  
Yusheng Qu ◽  
William A. Catterall ◽  
Todd Scheuer
Keyword(s):  
Sodium Channel ◽  
Local Anesthetic ◽  
Receptor Site ◽  
Differential Interaction ◽  
Α Subunits

Comparisons of voltage-gated sodium channel structures with open and closed gates and implications for state-dependent drug design

2018 ◽  
Vol 46 (6) ◽  
pp. 1567-1575 ◽  
Author(s):  
Giulia Montini ◽  
Jennifer Booker ◽  
Altin Sula ◽  
B.A. Wallace
Keyword(s):  
Drug Design ◽  
Sodium Channels ◽  
Rational Drug Design ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
State Dependent ◽  
Rational Drug ◽  
Sequence Homologies ◽  
Arcobacter Butzleri ◽  
Functional Consequences

Voltage-gated sodium channels (Navs) are responsible for the initiation of the action potential in excitable cells. Several prokaryotic sodium channels, most notably NavMs from Magnetococcus marinus and NavAb from Arcobacter butzleri, have been shown to be good models for human sodium channels based on their sequence homologies and high levels of functional similarities, including ion flux, and functional consequences of critical mutations. The complete full-length crystal structures of these prokaryotic sodium channels captured in different functional states have now revealed the molecular natures of changes associated with the gating process. These include the structures of the intracellular gate, the selectivity filter, the voltage sensors, the intra-membrane fenestrations, and the transmembrane (TM) pore. Here we have identified for the first time how changes in the fenestrations in the hydrophobic TM region associated with the opening of the intracellular gate could modulate the state-dependent ingress and binding of drugs in the TM cavity, in a way that could be exploited for rational drug design.

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