Molecular basis of species-specific expression of repolarizing K+ currents in the heart

2003 ◽  
Vol 285 (4) ◽  
pp. H1641-H1649 ◽  
Author(s):  
Stephen Zicha ◽  
Isaac Moss ◽  
Bruce Allen ◽  
Andras Varro ◽  
Julius Papp ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Protein Expression ◽  
Guinea Pigs ◽  
Delayed Rectifier ◽  
Important Species ◽  
Α Subunit ◽  
Delayed Rectifier Current ◽  
Mrna Concentration ◽  
Subunit Expression ◽  
Species Specific

There are important species-specific differences in K+ current profiles and arrhythmia susceptibility, but interspecies comparisons of K+ channel subunit expression are lacking. We quantified voltage-gated K+ channel (Kv) subunit mRNA and protein in rabbits, guinea pigs, and humans. Kv1.4, Kv4.2, and Kv4.3 mRNA was present in rabbits but undetectable in guinea pigs. MinK mRNA concentration in guinea pigs was almost threefold greater versus humans and 20-fold versus rabbits. MinK protein expression in guinea pigs was almost twofold that in humans and sixfold that in rabbits. KvLQT1 mRNA concentration was greatest in humans, and protein expression in humans was increased by ∼2- and ∼7-fold compared with values in rabbits and guinea pigs, respectively. The ether-a-go-go-related gene (ERG1) mRNA was more concentrated in humans, but ERG1 protein expression could not be compared across species because of epitope sequence differences. We conclude that important interspecies differences in cardiac K+ channel subunit expression exist and may contribute to the following: 1) lack of a transient outward current in the guinea pig (α-subunit transcription absent in the guinea pig heart); 2) small slow delayed rectifier current and torsades de pointes susceptibility in the rabbit (low-level minK expression); and 3) large slow component of the delayed rectifier current in the guinea pig (strong minK expression).

Patch-clamp recording in myenteric neurons of guinea pig small intestine

1992 ◽  
Vol 262 (6) ◽  
pp. G1074-G1078 ◽  
Author(s):  
L. V. Baidan ◽  
A. V. Zholos ◽  
M. F. Shuba ◽  
J. D. Wood
Keyword(s):  
Small Intestine ◽  
Patch Clamp ◽  
Guinea Pig ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Patch Clamp Recording ◽  
Myenteric Neurons ◽  
Delayed Rectifier Current ◽  
Outward Currents ◽  
Current Clamp Mode

The results of our research established the feasibility of applying patch-clamp methods in the study of the cellular neurophysiology of myenteric neurons enzymatically dissociated from adult guinea pig small intestine. Recording in current-clamp mode revealed two populations of neurons. One population discharged repetitively during depolarizing current pulses and displayed anodal-break excitation reminiscent of S/type 1 myenteric neurons. In the second population, spike discharge was limited to one or two spikes at the onset of depolarizing pulses and was similar to the behavior of AH/type 2 neurons. Recording in voltage-clamp mode revealed a complex of overlapping inward and outward whole cell currents. Fast and slow components of inward current were interpreted as sodium and calcium currents, respectively. Outward currents were blocked by cesium and consisted of components with properties of delayed rectifier current and A-type potassium current.

Quinidine elicits proarrhythmic changes in ventricular repolarization and refractoriness in guinea-pig

2013 ◽  
Vol 91 (4) ◽  
pp. 306-315 ◽  
Author(s):  
Oleg E. Osadchii
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Left Ventricular ◽  
Ventricular Repolarization ◽  
Monophasic Action Potential ◽  
Delayed Rectifier ◽  
Rate Dependent ◽  
Delayed Rectifier Current ◽  
Left Ventricular Chamber ◽  
The Right

Quinidine is a class Ia Na+ channel blocker that prolongs cardiac repolarization owing to the inhibition of IKr, the rapid component of the delayed rectifier current. Although quinidine may induce proarrhythmia, the contributing mechanisms remain incompletely understood. This study examined whether quinidine may set proarrhythmic substrate by inducing spatiotemporal abnormalities in repolarization and refractoriness. The monophasic action potential duration (APD), effective refractory periods (ERPs), and volume-conducted electrocardiograms (ECGs) were assessed in perfused guinea-pig hearts. Quinidine was found to produce the reverse rate-dependent prolongation of ventricular repolarization, which contributed to increased steepness of APD restitution. Throughout the epicardium, quinidine elicited a greater APD increase in the left ventricular chamber compared with the right ventricle, thereby enhancing spatial repolarization heterogeneities. Quinidine prolonged APD to a greater extent than ERP, thus extending the vulnerable window for ventricular re-excitation. This change was attributed to increased triangulation of epicardial action potential because of greater APD lengthening at 90% repolarization than at 30% repolarization. Over the transmural plane, quinidine evoked a greater ERP prolongation at endocardium than epicardium and increased dispersion of refractoriness. Premature ectopic beats and monomorphic ventricular tachycardia were observed in 50% of quinidine-treated heart preparations. In summary, abnormal changes in repolarization and refractoriness contribute greatly to proarrhythmic substrate upon quinidine infusion.

scholarly journals GDF-15 enhances intracellular Ca2+ by increasing Cav1.3 expression in rat cerebellar granule neurons

2016 ◽  
Vol 473 (13) ◽  
pp. 1895-1904 ◽  
Author(s):  
Jun-Mei Lu ◽  
Chang-Ying Wang ◽  
Changlong Hu ◽  
Yan-Jia Fang ◽  
Yan-Ai Mei
Keyword(s):  
Transforming Growth Factor ◽  
Mammalian Target Of Rapamycin ◽  
Transforming Growth Factor Β ◽  
Cerebellar Granule Neurons ◽  
Delayed Rectifier ◽  
Granule Neurons ◽  
Α Subunit ◽  
Cerebellar Granule ◽  
Subunit Expression ◽  
Ca2 Channels

GDF-15 (growth/differentiation factor 15) is a novel member of the TGF (transforming growth factor)-β superfamily that has critical roles in the central and peripheral nervous systems. We reported previously that GDF-15 increased delayed rectifier outward K+ currents and Kv2.1 α subunit expression through TβRII (TGF-β receptor II) to activate Src kinase and Akt/mTOR (mammalian target of rapamycin) signalling in rat CGNs (cerebellar granule neurons). In the present study, we found that treatment of CGNs with GDF-15 for 24 h increased the intracellular Ca2+ concentration ([Ca2+]i) in response to membrane depolarization, as determined by Ca2+ imaging. Whole-cell current recordings indicated that GDF-15 increased the inward Ca2+ current (ICa) without altering steady-state activation of Ca2+ channels. Treatment with nifedipine, an inhibitor of L-type Ca2+ channels, abrogated GDF-15-induced increases in [Ca2+]i and ICa. The GDF-15-induced increase in ICa was mediated via up-regulation of the Cav1.3 α subunit, which was attenuated by inhibiting Akt/mTOR and ERK (extracellular-signal-regulated kinase) pathways and by pharmacological inhibition of Src-mediated TβRII phosphorylation. Given that Cav1.3 is not only a channel for Ca2+ influx, but also a transcriptional regulator, our data confirm that GDF-15 induces protein expression via TβRII and activation of a non-Smad pathway, and provide novel insight into the mechanism of GDF-15 function in neurons.

scholarly journals Cell swelling has differential effects on the rapid and slow components of delayed rectifier potassium current in guinea pig cardiac myocytes.

1995 ◽  
Vol 106 (6) ◽  
pp. 1151-1170 ◽  
Author(s):  
S A Rees ◽  
J I Vandenberg ◽  
A R Wright ◽  
A Yoshida ◽  
T Powell
Keyword(s):  
Guinea Pig ◽  
Potassium Current ◽  
Mean Value ◽  
Cell Swelling ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Differential Effects ◽  
Delayed Rectifier Current ◽  
Delayed Rectifier Potassium Current ◽  
Ionic Conductances

Cell swelling has been shown to cause activation of a variety of cardiac sarcolemmal ionic conductances including potassium channels. The aim of this study was to investigate the effect of swelling on the two subtypes of delayed rectifier potassium current (IKr and IKs) in single guinea pig myocytes using the whole-cell configuration of the patch clamp technique. When the holding potential was set at -40 mV and stepped to +40 mV for 1 s under isoosmotic conditions (300 mOsm) a delayed rectifier current (IK) was activated (0.86 +/- 0.05 nA; n = 43). Switching to a hypoosmotic solution (200 mOsm) caused a rapid increase in IK to a mean value of 1.43 +/- 0.10 nA (p < 0.05; n = 43). The effect of swelling on the two subtypes of IK was studied by analysis of deactivating tail currents using an envelope of tails protocol (stepping from -40 to +40 mV for 18 different pulse durations between 50 ms and 2.9 s; n = 16). Swelling caused a decrease in current amplitude measured at the end of the pulse (and IKtail) at short durations (< or = 150 ms) however, when the pulse duration was > 1 s swelling caused a significant increase in current. Using a pulse protocol to measure IKr with minimal contamination by IKs (voltage step from -40 to -10 mV for 250 ms) a 50-100 pA current was elicited which could be completely blocked by dofetilide (0.2 microM; n = 3). Introduction of hypoosmotic solution caused a significant decrease in IKr and when dofetilide (0.2 or 1.0 microM) was introduced the current remaining was decreased further (p < 0.05; n = 5), but was not completely blocked, thus suggesting that swelling had decreased the ability of dofetilide to block IKr. Similar results were obtained over a range of dofetilide concentrations and with a second IKr blocker, La3+. In Ca(2+)-free external solutions, pulsing to -10 mV for 500 ms to measure IKr in the absence of IKs, and to +60 mV for 5 s (with 0.2 microM dofetilide) to evoke only IKs, it was clear that swelling significantly increased IKs (pulse and tail currents) and decreased IKr. In addition, when measured using the perforated patch method, swelling modulated IKt and IKs in a similar fashion. We conclude that swelling has differential effects on the subtypes of the classical cardiac IK, which may have important implications in our understanding of the mechanisms underlying ischaemia- and reperfusion-induced arrhythmogenesis.

scholarly journals Screening for Mutations and Polymorphisms in the Genes KCNH2 and KCNE2 Encoding the Cardiac HERG/MiRP1 Ion Channel: Implications for Acquired and Congenital Long Q-T Syndrome

2001 ◽  
Vol 47 (8) ◽  
pp. 1390-1395 ◽  
Author(s):  
Lars Allan Larsen ◽  
Paal Skytt Andersen ◽  
Jørgen Kanters ◽  
Ida Hastrup Svendsen ◽  
Joes Ramsøe Jacobsen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ion Channel ◽  
Single Strand Conformation Polymorphism ◽  
K Channel ◽  
Delayed Rectifier ◽  
Nucleotide Polymorphisms ◽  
Amino Acid Polymorphism ◽  
Α Subunit ◽  
Delayed Rectifier Current ◽  
Gene Coding

Abstract Background: The voltage-gated, rapid-delayed rectifier current (IKr) is important for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the α-subunit HERG and KCNE2 for the β-subunit MiRP1, cause acquired and congenital long Q-T syndrome (LQTS) and other cardiac arrhythmias. Methods: We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The method was used to screen 40 unrelated LQTS patients. Results: Eleven mutations, of which six were novel, were found in KCNH2. Interestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing the need to examine the entire gene when screening for mutations. No mutations were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. Conclusions: The potential role of rare polymorphisms in the HERG/MiRP1 K+-channel should be clarified with respect to drug interactions and susceptibility to arrhythmia and sudden death.

The Effects of Homologous Testicular and Brain and Heterologous Testicular Homogenates combined with Adjuvant upon the Testes of Guinea-Pigs

Development ◽  
1958 ◽  
Vol 6 (1) ◽  
pp. 94-104
Author(s):  
Seymour Katsh ◽  
David W. Bishop
Keyword(s):  
Guinea Pig ◽  
Antibody Production ◽  
Guinea Pigs ◽  
Complement Fixation ◽  
Closely Related Species ◽  
Common Antigens ◽  
Heterologous Sperm ◽  
Species Specific ◽  
Sperm Immobilization ◽  
Ram Sperm

Numerous efforts have demonstrated antibody production after injection of spermatozoa into animals of the same species. For example, Metalnikoff (1900) and Kennedy (1924) reported anti-guinea-pig sperm ‘toxins’ in guinea-pigs; McCartney (1923) noted anti-rat sperm ‘toxins’ in rats; Pfeiffer (1905), Dittler (1920), and Pommerenke (1928) demonstrated anti-rabbit ‘spermatotoxins’ in rabbits. Antibody production against heterologous sperm has also been disclosed: Mudd & Mudd (1929) injected human, guinea-pig, bull, and ram sperm into rabbits and reported that the resultant antibodies were species specific. The absoluteness of specificity, both organ and species, however, has been qualified by the study of Lewis (1934), who found that brain and testicles possess common antigens, and Henle (1938) has extended Mudd & Mudd's (1929) observations on cross-reaction between sperm of closely related species. In the above-mentioned studies the methods for determining antisperm activity of antisera included complement-fixation, sperm-immobilization, agglutination, and precipitin tests.

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