Two types of modified cardiac Na + channels after cytosolic interventions at the α-subunit capable of removing Na + inactivation

1997 ◽  
Vol 25 (3) ◽  
pp. 189-200 ◽  
Author(s):  
I. Benz ◽  
W. Beck ◽  
W. Kraas ◽  
D. Stoll ◽  
G. Jung ◽  
...  
Keyword(s):  
Na Channels ◽  
Α Subunit ◽  
Na Inactivation

scholarly journals The Human Heart and Rat Brain IIA Na+ Channels Interact with Different Molecular Regions of the β1 Subunit

2002 ◽  
Vol 120 (6) ◽  
pp. 887-895 ◽  
Author(s):  
Thomas Zimmer ◽  
Klaus Benndorf
Keyword(s):  
Rat Brain ◽  
Human Heart ◽  
Xenopus Oocytes ◽  
Extracellular Domain ◽  
Na Channel ◽  
Na Channels ◽  
Membrane Anchor ◽  
Α Subunit ◽  
Extracellular Region ◽  
Recovery From Inactivation

The α subunit of voltage-gated Na+ channels of brain, skeletal muscle, and cardiomyocytes is functionally modulated by the accessory β1, but not the β2 subunit. In the present study, we used β1/β2 chimeras to identify molecular regions within the β1 subunit that are responsible for both the increase of the current density and the acceleration of recovery from inactivation of the human heart Na+ channel (hH1). The channels were expressed in Xenopus oocytes. As a control, we coexpressed the β1/β2 chimeras with rat brain IIA channels. In agreement with previous studies, the β1 extracellular domain sufficed to modulate IIA channel function. In contrast to this, the extracellular domain of the β1 subunit alone was ineffective to modulate hH1. Instead, the putative membrane anchor plus either the intracellular or the extracellular domain of the β1 subunit was required. An exchange of the β1 membrane anchor by the corresponding β2 subunit region almost completely abolished the effects of the β1 subunit on hH1, suggesting that the β1 membrane anchor plays a crucial role for the modulation of the cardiac Na+ channel isoform. It is concluded that the β1 subunit modulates the cardiac and the neuronal channel isoforms by different molecular interactions: hH1 channels via the membrane anchor plus additional intracellular or extracellular regions, and IIA channels via the extracellular region only.

Genetic polymorphisms of SCNA9 as predictive markers of oxaliplatin-induced neuropathy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9073-9073
Author(s):  
Maria Sereno ◽  
Gerardo Gutierrez-Gutierrez ◽  
Cristina Rodriguez-Antona ◽  
Lara Sanchez ◽  
Cesar gomez Lopez ◽  
...  
Keyword(s):  
Pain Perception ◽  
Dose Intensity ◽  
University Hospital ◽  
Na Channels ◽  
Digestive Cancer ◽  
Α Subunit ◽  
Nociceptive Neurons ◽  
Pcr Rflp ◽  
The Mean ◽  
Dose Limiting Toxicity

9073 Background: Oxaliplatin (OXL) is an active drug in digestive tumors. Oxaliplatin induced peripheral neuropathy (OIN) is the main dose limiting toxicity. Around 60-80% of patients developed a mild cold-induced neurotoxicity that used to disappear few days after but in 15% became a persistent neuropathy. The pathophysiology of oxaliplatin-induced neuropathy (OIN) remains unclear, preclinical studies suggest involvement of voltage Na channels. SCN9A gene codifies to Na channels α subunit highly expressed in nociceptive neurons. Mutations in SCN9A are involved in alterations in neuropatic pain perception. This study tried to identify if variants in SCN9A could be associated to a higher risk to OIN. Methods: Serum were obtained from 100 patients with digestive cancer (colorectal, gastric, pancreatic and bile duct) treated with OXL (adjuvant or advanced setting) in Infanta Sofía University Hospital. No diabetes or hypotiroidism were detected. Patients were divided in two groups according to the development of OIN: Arm A 50 patients diagnosed of grade 2-3 OIN after 6 courses and Arm B 50 with no OIN. The evaluation of severity of the OIN by a neurologist included a classification according to NCI-CTC and OSNS scales and conduction studies. Genomic DNA was isolated from serum and variants of SCN9A were analyzed by PCR-RFLP. The relation between SCN9A genotype and the development of severe OIN was the primary aim Results: One hundred patients were enrolled between May 2010-November 2011. 56 (56%) females and 44 (44%) males; mean age was 62; mean ECOG was 1; primary tumor were colorectal 81 pts (81%), gastric 10 (10%); 8 (8%) pancreto-biliar and anus 1(1%). Stage were classified in localized 65 (65%) and advanced (35%). The chemotherapy regimen included: 94 (94%) XELOX, 1 (1%) XELOX-Herceptin and 5 (5%) EOX regimen. The mean of cycles were 7 (1-14). Mean OXL dose intensity was 100mg/m2.The mean PFS was 23 months. High expression of SCN9A variants were detected in patients 26/50, 52% arm A and in 5/50, 10% arm B patients, suggesting a possible relationship beetwen the development of OIN and SCN9A genotype (p=0.04). Conclusions: SCN9A polimorphysms may help to identify those patients with a higher risk to develop oxaliplatin induced neuropathy.

scholarly journals Potent block of inactivation-deficient Na+ channels by n-3 polyunsaturated fatty acids

2006 ◽  
Vol 290 (2) ◽  
pp. C362-C370 ◽  
Author(s):  
Yong-Fu Xiao ◽  
Li Ma ◽  
Sho-Ya Wang ◽  
Mark E. Josephson ◽  
Ging Kuo Wang ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Inhibitory Effect ◽  
Deficient Mutant ◽  
Na Channels ◽  
Mutant Channel ◽  
Α Subunit ◽  
Voltage Gated ◽  
Steady State Inactivation

A voltage-gated, small, persistent Na+ current ( INa) has been shown in mammalian cardiomyocytes. Hypoxia potentiates the persistent INa that may cause arrhythmias. In the present study, we investigated the effects of n-3 polyunsaturated fatty acids (PUFAs) on INa in HEK-293t cells transfected with an inactivation-deficient mutant (L409C/A410W) of the α-subunit (hH1α) of human cardiac Na+ channels (hNav1.5) plus β1-subunits. Extracellular application of 5 μM eicosapentaenoic acid (EPA; C20:5n-3) significantly inhibited INa. The late portion of INa ( INa late, measured near the end of each pulse) was almost completely suppressed. INa returned to the pretreated level after washout of EPA. The inhibitory effect of EPA on INa was concentration dependent, with IC50 values of 4.0 ± 0.4 μM for INa peak ( INa peak) and 0.9 ± 0.1 μM for INa late. EPA shifted the steady-state inactivation of INa peak by −19 mV in the hyperpolarizing direction. EPA accelerated the process of resting inactivation of the mutant channel and delayed the recovery of the mutated Na+ channel from resting inactivation. Other polyunsaturated fatty acids, docosahexaenoic acid, linolenic acid, arachidonic acid, and linoleic acid, all at 5 μM concentration, also significantly inhibited INa. In contrast, the monounsaturated fatty acid oleic acid or the saturated fatty acids stearic acid and palmitic acid at 5 μM concentration had no effect on INa. Our data demonstrate that the double mutations at the 409 and 410 sites in the D1–S6 region of hH1α induce inactivation-deficient INa and that n-3 PUFAs inhibit mutant INa.

scholarly journals Effect of sea anemone toxins on the sodium inactivation process in crayfish axons.

1983 ◽  
Vol 81 (3) ◽  
pp. 305-323 ◽  
Author(s):  
A Warashina ◽  
S Fujita
Keyword(s):  
Time Course ◽  
Early Stage ◽  
Sea Anemone ◽  
Na Channels ◽  
Current Profile ◽  
Anemonia Sulcata ◽  
Sodium Inactivation ◽  
Na Inactivation ◽  
Inactivation Process ◽  
Kinetics Of

The effect of sea anemone toxins from Parasicyonis actinostoloides and Anemonia sulcata on the Na conductance in crayfish giant axons was studied under voltage-clamp conditions. The toxin slowed the Na inactivation process without changing the kinetics of Na activation or K activation in an early stage of the toxin effect. An analysis of the Na current profile during the toxin treatment suggested an all-or-none modification of individual Na channels. Toxin-modified Na channels were partially inactivated with a slower time course than that of the normal inactivation. This slow inactivation in steady state decreased in its extent as the membrane was depolarized to above -45 mV, so that practically no inactivation occurred at the membrane potentials as high as +50 mV. In addition to inhibition of the normal Na inactivation, prolonged toxin treatment induced an anomalous closing in a certain population of Na channels, indicated by very slow components of the Na tail current. The observed kinetic natures of toxin-modified Na channels were interpreted based on a simple scheme which comprised interconversions between functional states of Na channels. The voltage dependence of Parasicyonis toxin action, in which depolarization caused a suppression in development of the toxin effect, was also investigated.

Point Mutations in α-Subunit of Human Cardiac Na+ Channels Alter Na+ Current Kinetics

2001 ◽  
Vol 281 (1) ◽  
pp. 45-52 ◽  
Author(s):  
Yong-Fu Xiao ◽  
Qingen Ke ◽  
Sho-Ya Wang ◽  
Yinke Yang ◽  
Ging Kuo Wang ◽  
...  
Keyword(s):  
Point Mutations ◽  
Na Channels ◽  
Na Current ◽  
Α Subunit

scholarly journals The Position of the Fast-Inactivation Gate during Lidocaine Block of Voltage-gated Na+ Channels

1999 ◽  
Vol 113 (1) ◽  
pp. 7-16 ◽  
Author(s):  
Vasanth Vedantham ◽  
Stephen C. Cannon
Keyword(s):  
Sodium Channel ◽  
Crucial Role ◽  
Ionic Current ◽  
Na Channel ◽  
Dependent Manner ◽  
Na Channels ◽  
Fast Inactivation ◽  
Adult Skeletal Muscle ◽  
Α Subunit ◽  
Voltage Gated

Lidocaine produces voltage- and use-dependent inhibition of voltage-gated Na+ channels through preferential binding to channel conformations that are normally populated at depolarized potentials and by slowing the rate of Na+ channel repriming after depolarizations. It has been proposed that the fast-inactivation mechanism plays a crucial role in these processes. However, the precise role of fast inactivation in lidocaine action has been difficult to probe because gating of drug-bound channels does not involve changes in ionic current. For that reason, we employed a conformational marker for the fast-inactivation gate, the reactivity of a cysteine substituted at phenylalanine 1304 in the rat adult skeletal muscle sodium channel α subunit (rSkM1) with [2-(trimethylammonium)ethyl]methanethiosulfonate (MTS-ET), to determine the position of the fast-inactivation gate during lidocaine block. We found that lidocaine does not compete with fast-inactivation. Rather, it favors closure of the fast-inactivation gate in a voltage-dependent manner, causing a hyperpolarizing shift in the voltage dependence of site 1304 accessibility that parallels a shift in the steady state availability curve measured for ionic currents. More significantly, we found that the lidocaine-induced slowing of sodium channel repriming does not result from a slowing of recovery of the fast-inactivation gate, and thus that use-dependent block does not involve an accumulation of fast-inactivated channels. Based on these data, we propose a model in which transitions along the activation pathway, rather than transitions to inactivated states, play a crucial role in the mechanism of lidocaine action.

Sign in / Sign up

Export Citation Format

Share Document