Assay Technologies: Techniques Available for Quantifying Drug–Channel Interactions

2006 ◽  
pp. 37-63 ◽  
Author(s):  
Derek Leishman ◽  
Gareth Waldron
Keyword(s):  
Channel Interactions

scholarly journals On the Importance of Atomic Fluctuations, Protein Flexibility, and Solvent in Ion Permeation

2004 ◽  
Vol 124 (6) ◽  
pp. 679-690 ◽  
Author(s):  
Toby W. Allen ◽  
O.S. Andersen ◽  
Benoit Roux
Keyword(s):  
Ion Channel ◽  
Protein Function ◽  
Channel Model ◽  
Protein Structures ◽  
Thermal Fluctuations ◽  
Model Parameters ◽  
Ion Permeation ◽  
Model Calculations ◽  
Channel Interactions ◽  
Solvent Molecules

Proteins, including ion channels, often are described in terms of some average structure and pictured as rigid entities immersed in a featureless solvent continuum. This simplified view, which provides for a convenient representation of the protein's overall structure, incurs the risk of deemphasizing important features underlying protein function, such as thermal fluctuations in the atom positions and the discreteness of the solvent molecules. These factors become particularly important in the case of ion movement through narrow pores, where the magnitude of the thermal fluctuations may be comparable to the ion pore atom separations, such that the strength of the ion channel interactions may vary dramatically as a function of the instantaneous configuration of the ion and the surrounding protein and pore water. Descriptions of ion permeation through narrow pores, which employ static protein structures and a macroscopic continuum dielectric solvent, thus face fundamental difficulties. We illustrate this using simple model calculations based on the gramicidin A and KcsA potassium channels, which show that thermal atomic fluctuations lead to energy profiles that vary by tens of kcal/mol. Consequently, within the framework of a rigid pore model, ion-channel energetics is extremely sensitive to the choice of experimental structure and how the space-dependent dielectric constant is assigned. Given these observations, the significance of any description based on a rigid structure appears limited. Creating a conducting channel model from one single structure requires substantial and arbitrary engineering of the model parameters, making it difficult for such approaches to contribute to our understanding of ion permeation at a microscopic level.

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 SUMOylation regulates USP5-Cav3.2 calcium channel interactions

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Agustin Garcia-Caballero ◽  
Fang-Xiong Zhang ◽  
Lina Chen ◽  
Said M’Dahoma ◽  
Junting Huang ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Channel Interactions
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