Different Types Of Potassium Channels Research Articles

Physiological role of potassium channels in mammalian germ cell differentiation, maturation, and capacitation

Ion channels are essential for differentiation and maturation of germ cells, and even for fertilization in mammals. Different types of potassium channels have been identified, which are grouped into voltage-gated channels (Kv), ligand-gated channels (Kligand ), inwardly rectifying channels (Kir ), and tandem pore domain channels (K2P ). The present review includes recent findings on the role of potassium channels in sperm physiology of mammals. While most studies conducted thus far have been focused on the physiological role of voltage- (Kv1, Kv3, and Kv7) and calcium-gated channels (SLO1 and SLO3) during sperm capacitation, especially in humans and rodents, little data about the types of potassium channels present in the plasma membrane of differentiating germ cells exist. In spite of this, recent evidence suggests that the content and regulation mechanisms of these channels vary throughout spermatogenesis. Potassium channels are also essential for the regulation of sperm cell volume during epididymal maturation and for preventing premature membrane hyperpolarization. It is important to highlight that the nature, biochemical properties, localization, and regulation mechanisms of potassium channels are species-specific. In effect, while SLO3 is the main potassium channel involved in the K+ current during sperm capacitation in rodents, different potassium channels are implicated in the K+ outflow and, thus, plasma membrane hyperpolarization during sperm capacitation in other mammalian species, such as humans and pigs. Potassium conductance is essential for male fertility, not only during sperm capacitation but throughout the spermiogenesis and epididymal maturation.

Methodological challenges in using human umbilical artery as a model for in vitro studies.

What is the central question of this study? What are the biggest challenges in performing in vitro studies on isolated human umbilical arteries? What is the main finding and its importance? The protocols presented in this study indicate some potential outcomes important for interpretation of the vascular responsivities of human umbilical arteries and could be useful for planning future in vitro studies with human umbilical arteries. Human umbilical artery (HUA) preparations are of particular importance for in vitro studies on isolated blood vessels because their sampling is not risky for the patient, and they can provide the closest possible impression of changes related to the uteroplacental circulation during pre-eclampsia. Using organ bath techniques, useful experimental protocols are provided for measuring some pathophysiological phenomena in the vascular responses of HUAs. Several vasoconstrictors (serotonin, prostaglandin F and phenylephrine) and vasodilators (acetylcholine and minoxidil) were seleted for determination of their vasoactivity in HUAs. The role of L-type voltage-operated calcium channels and different types of potassium channels (KATP , BKCa and KV ) were assessed, as was the impact of homocysteine. Serotonin was confirmed to be the most potent vasoconstrictor, while acetylcholine and phenylephrine caused variability in the relaxation and contraction response of HUA, respectively. The observed increase in serotonin-induced contraction and a decrease in minoxidil-induced relaxation in the presence of homocysteine suggested its procontractile effect on HUA preparations. Using selective blockers, it was determined that KATP and KV channels participate in the minoxidil-induced relaxation, while L-type voltage-dependent Ca2+ channels play an important role in the serotonin-induced contraction. The presented protocols reveal some of the methodological challenges related to HUA preparations and indicate potential outcomes in interpreting the vascular effects of the investigated substances, both in physiological conditions and in the homocysteine-induced pre-eclampsia model.

On the use of Kolmogorov equations for determining ion channels characteristics

The paper proposes a method for determination of the dynamic properties of conduction within voltage-gated ion channels with several sequentially located energy barriers named gate particles using a theory of Markov random processes in continuous time and with a discrete state space. The number of states was taken equal to the number of energy barriers in the channel plus one. If the hypothesis that random flows switching gate particles between an open and a closed are Poisson process, is true, then mathematical description of the system’s state of similar channels can be a system of Kolmogorov linear differential equations for state probabilities. Using this model and based on Volt-Clamp test results, published in open access journals, it is possible to find out how fixed values of membrane potential depend on the intensities of Poisson process for different types of potassium channels. Function parameters, that describe the intensity of ion transition across the channel, in the Kolmogorov equation can be restored using the generalized least squares method. This paper contains the examples of determining the intensities of transitions for two types of voltage-dependent potassium channels known as «delayed rectifiier potassium channels» (IKdr, two identical activation gate particles) and channels with fast activation and inactivation processes (IKa, three identical activation and one inactivation gate particles). It is shown that channel activation and deactivation is described by solving the general Kolmogorov equation.

What Is the Role of Potassium Channels in Ataxia?

There is emerging evidence from experimental models that different types of potassium channels have a major role in shaping the electrophysiologic properties of Purkinje cells. Studies in mouse models of spinocerebellar ataxias (SCAs) indicate that altered Purkinje cell firing and excessive accumulation of intracellular calcium are 2 major mechanisms of cerebellar ataxia.1-6 Potassium channel mutations are an increasingly recognized cause of dominantly inherited SCA7-11 and can also manifest with episodic ataxia.12 These findings indicate that potassium channels provide a potential therapeutic target in these disorders.

Identification of a novel potassium channel (GiK) as a potential drug target in Giardia lamblia: Computational descriptions of binding sites.

BackgroundThe protozoan Giardia lamblia is the causal agent of giardiasis, one of the main diarrheal infections worldwide. Drug resistance to common antigiardial agents and incidence of treatment failures have increased in recent years. Therefore, the search for new molecular targets for drugs against Giardia infection is essential. In protozoa, ionic channels have roles in their life cycle, growth, and stress response. Thus, they are promising targets for drug design. The strategy of ligand-protein docking has demonstrated a great potential in the discovery of new targets and structure-based drug design studies.MethodsIn this work, we identify and characterize a new potassium channel, GiK, in the genome of Giardia lamblia. Characterization was performed in silico. Because its crystallographic structure remains unresolved, homology modeling was used to construct the three-dimensional model for the pore domain of GiK. The docking virtual screening approach was employed to determine whether GiK is a good target for potassium channel blockers.ResultsThe GiK sequence showed 24–50% identity and 50–90% positivity with 21 different types of potassium channels. The quality assessment and validation parameters indicated the reliability of the modeled structure of GiK. We identified 110 potassium channel blockers exhibiting high affinity toward GiK. A total of 39 of these drugs bind in three specific regions.DiscussionThe GiK pore signature sequence is related to the small conductance calcium-activated potassium channels (SKCa). The predicted binding of 110 potassium blockers to GiK makes this protein an attractive target for biological testing to evaluate its role in the life cycle of Giardia lamblia and potential candidate for the design of novel antigiardial drugs.

The Action of Smooth Muscle Cell Potassium Channels in the Pathology of Pulmonary Arterial Hypertension.

Many different types of potassium channels with various functions exist in pulmonary artery smooth muscle cells, contributing to many physiological actions and pathological conditions. The deep involvement of these channels in the onset and exacerbation of pulmonary arterial hypertension (PAH) also continues to be revealed. In 2013, KCNK3 (TASK1), which encodes a type of two-pore domain potassium channel, was shown to be a predisposing gene for PAH by genetic mutation, and it was added to the PAH classification at the Fifth World Symposium on Pulmonary Hypertension (Nice International Conference). Decreased expression and inhibited activity of voltage-gated potassium channels, particularly KCNA5 (Kv1.5), are also seen in PAH, regardless of the cause, and facilitation of pulmonary arterial contraction and vascular remodeling has been shown. The calcium-activated potassium channels seen in smooth muscle cells also change from BKca (Kca1.1) to IKca (Kca3.1) predominance in PAH due to transformation and have effects including the facilitation of smooth muscle cell migration, enhancement of proliferation, and inhibition of apoptosis. Elucidation of these roles for potassium channels in pulmonary vasoconstriction and remodeling may help bring new therapeutic strategies into view.

Electrophysiological Characterization of Ts6 and Ts7, K+ Channel Toxins Isolated through an Improved Tityus serrulatus Venom Purification Procedure

In Brazil, Tityus serrulatus (Ts) is the species responsible for most of the scorpion related accidents. Among the Ts toxins, the neurotoxins with action on potassium channels (α-KTx) present high interest, due to their effect in the envenoming process and the ion channel specificity they display. The α-KTx toxins family is the most relevant because its toxins can be used as therapeutic tools for specific target cells. The improved isolation method provided toxins with high resolution, obtaining pure Ts6 and Ts7 in two chromatographic steps. The effects of Ts6 and Ts7 toxins were evaluated in 14 different types of potassium channels using the voltage-clamp technique with two-microelectrodes. Ts6 toxin shows high affinity for Kv1.2, Kv1.3 and Shaker IR, blocking these channels in low concentrations. Moreover, Ts6 blocks the Kv1.3 channel in picomolar concentrations with an IC50 of 0.55 nM and therefore could be of valuable assistance to further designing immunosuppressive therapeutics. Ts7 toxin blocks multiple subtypes channels, showing low selectivity among the channels analyzed. This work also stands out in its attempt to elucidate the residues important for interacting with each channel and, in the near future, to model a desired drug.

Role of different types of potassium channels in the relaxation of corpus cavernosum induced by resveratrol

Background:Resveratrol (RVT), one of the most commonly employed dietary polyphenol, is used in traditional Japanese and Chinese medicine for treatment of cardiovascular diseases. Recently, we have shown that RVT has a potent relaxant effect on rat corpus cavernosum via endothelium-dependent and -independent mechanisms.Objective:The present study addressed the question whether different types of potassium channels are involved in the endothelium-dependent and -independent mechanism of corpus cavernosum relaxation induced by RVT.Materials and Methods:Strips of corpus cavernosum from rats were mounted in an organ-bath system for isometric tension studies.Results:RVT (1-100 μmol/L) produced concentration-dependent relaxation responses in rat corpus cavernosum pre-contracted by phenylephrine. The non-selective potassium channels blocker tetraethylammonium chloride (TEA, 10 mmol/L), ATP-sensitive potassium (KATP) channels blocker glibenclamide (10 μmol/L), and inward rectifier potassium (Kir) channels inhibitor barium chloride (BaCl2, 30 μmol/L) caused a significant inhibition on the relaxation response to RVT, whereas voltage-dependent potassium channels inhibitor 4-aminopyridine (4-AP, 1 mmol/L), and large conductance calcium-activated potassium (BKCa) channels inhibitor iberiotoxin (IbTX, 0.1 μmol/L) did not significantly alter relaxant responses of corpus cavernosum strips to RVT. In addition, relaxant responses to RVT did not significantly inhibited by the combination of selective inhibitors of small and intermediate conductance BKCa channels (0.1 μmol/L charybdotoxin and 1 μmol/L apamin, respectively).Conclusion:These results demonstrated that endothelial small and intermediate conductance BKCa channels are not thought to be an important role in RVT-induced endothelium-dependent relaxation of corpus cavernosum. The endothelium-independent corpus cavernosum relaxation induced by RVT is seems to largely depend on Kir channels and KATP channels in corporal tissue.

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

Involvement of different types of potassium channels in the antidepressant-like effect of ascorbic acid in the mouse tail suspension test

Considering that the administration of ascorbic acid elicits an antidepressant-effect in mice by a mechanism which involves an interaction with N-methyl-d-aspartate receptors and the l-arginine-nitric oxide-cGMP pathway and taking into account that the stimulation of this pathway is associated with the activation of potassium (K+) channels, this study investigated the involvement of different types of K+ channels on the effect of ascorbic acid in the mouse tail suspension test (TST). Intracerebroventricular administration of tetraethylammonium (TEA, a non-specific blocker of K+ channels, 25pg/site), glibenclamide (an ATP-sensitive K+ channel blocker, 0.5pg/site), charybdotoxin (a large- and intermediate conductance calcium-activated K+ channel blocker, 25pg/site) or apamin (a small-conductance calcium-activated K+ channel blocker, 10pg/site) was able to produce a synergistic effect with a sub-effective dose of ascorbic acid (0.1mg/kg) given orally (p.o.). The antidepressant-like effect of ascorbic acid (1mg/kg, p.o.) in the TST was prevented by the pre-treatment of mice with cromakalim (a K+ channel opener, 10μg/site, i.c.v.) and minoxidil (10μg/site, i.c.v.). Moreover, cromakalim abolished the synergistic effect elicited by the combined treatment with sub-effective doses of ascorbic acid and 7-nitroindazole. The administration of the K+ channel modulators alone or in combination with ascorbic acid did not affect the locomotion of mice. Together, our results show that the antidepressant-like effect of ascorbic acid in the TST may involve, at least in part, the modulation of neuronal excitability, via inhibition of K+ channels.

Role of different types of potassium channels and peroxisome proliferator-activated receptors γ in the antidepressant-like activity of bis selenide in the mouse tail suspension test

In the present study we investigated the role of potassium (K+) channels and peroxisome proliferator-activated receptor gamma (PPARγ) in the antidepressant-like effect of bis selenide in the mouse tail suspension test (TST). Intracerebroventricular (i.c.v.) pretreatment with tetraethyl ammonium (TEA, a non-specific inhibitor of K+ channels, 25pg/site), glibenclamide (an ATP-sensitive K+ channel inhibitor, 0.5pg/site), charybdotoxin (a large and intermediate conductance calcium-activated K+ channel inhibitor, 25pg/site) or apamin (a small-conductance calcium-activated K+ channel inhibitor, 10pg/site) produced a synergistic action with a sub effective dose of bis selenide (0.1mg/kg, per oral – p.o.). Picrotoxin (1mg/kg, intraperitoneally – i.p.) pretreatment did not prevent the reduction in immobility time elicited by bis selenide (1mg/kg, p.o.) in the TST. The reduction in the immobility time elicited by an effective dose of bis selenide (1mg/kg, p.o.) was prevented by the pretreatment of mice with cromakalim, minoxidil (K+ channel openers, 10μg/site, i.c.v.) and GW 9662 (a PPARγ antagonist, 10μg/site, i.c.v.). The findings clearly suggest that an acute oral dose of bis selenide produced an antidepressant-like effect in the mouse TST by a mechanism that involves the K+ channels and PPARγ receptors.

Involvement of different types of potassium channels in the antidepressant-like effect of tramadol in the mouse forced swimming test

Administration of tramadol elicited an antidepressant-like effect in the rat forced swimming test (FST) by a mechanism dependent on the inhibition of the L-arginine-nitric oxide (NO)-guanylate cyclase pathway. Since it has been reported that NO can activate different types of potassium (K +) channels in several tissues, the present study investigated the possibility of synergistic interactions between different types of K + channel inhibitors and tramadol in the mouse FST. Intracerebroventricular pretreatment of mice with tetraethylammonium (TEA, a non-specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channel inhibitor, 0.5 pg/site) or charybdotoxin (a large- and intermediate conductance calcium-activated K + channel inhibitor, 25 pg/site) was able to produce a synergistic action of a subeffective dose of tramadol (1 mg/kg, p.o.). Conversely, pretreatment with apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site) did not modify the action of a subeffective dose of tramadol (1 mg/kg, p.o.). Administration of tramadol and the K + channel inhibitors, alone or in combination, did not affect the number of crossings and rearings in the open field test (OFT). Reduction in the immobility time elicited by an active dose of tramadol (40 mg/kg, p.o.) in the FST was prevented by pretreatment of mice with cromakalim (a K + channel opener, 10 µg/site, i.c.v.), without affecting the number of crossings and rearings in the OFT. Thus, our findings clearly suggest that oral acute administration of tramadol produces antidepressant-like effect on the FST in mice by a mechanism that involves the K + channels.

Novel α-KTx Sites in the BK Channel and Comparative Sequence Analysis Reveal Distinguishing Features of the BK and KV Channel Outer Pore

The alpha-KTx peptide toxins inhibit different types of potassium channels by occluding the outer channel pore composed of four identical alpha subunits. The large-conductance, calcium-activated (BK or Slo1) and voltage-dependent (KV) potassium channels differ in their specificity for the different alpha-KTx subfamilies. While many different alpha-KTx subfamilies of different sizes inhibit KV1 channels with high affinity, only one subfamily, alpha-KTx 1.x, inhibits BK channels with high affinity. Two solvent-exposed regions of the outer pore that influence alpha-KTx binding, the turret and loop, display high sequence variability among different potassium channels and may contribute to differences in alpha-KTx specificity. While these alpha-KTx domains have been studied in KV1 channels, little is known about the corresponding BK alpha-KTx domains. To define alpha-KTx sites in the BK outer pore, we examined the effect of 19 outer pore mutations on specific binding of 125I-labeled iberiotoxion (IbTX or alpha-KTx 1.3) and on their cell-surface expression. Similar to alpha-KTx sites in the Shaker KV1 loop, site-directed mutations in the BK loop disrupted specific IbTX binding. In contrast, mutations in the BK turret region revealed three novel alpha-KTx sites, Q267, N268, and L272, which are distinct from alpha-KTx sites in the KV1 turret. The BK turret region shows no sequence identity with KV1 and MthK turrets of known 3D structure. To define the BK turret, we used secondary structure prediction methods that incorporated information from sequence alignment of 30 different Slo1 and Slo3 turret sequences from 5 of the 7 major animal phyla representing 27 different species. Results of this analysis suggest that the BK turret contains 18 amino acids and is defined by a cluster of strictly conserved polar residues at the N-terminal side of the turret. Thus, the BK turret is predicted to have six more amino acids than the KV1 turret. Results of this work suggest that BK and KV1 outer pores have a similar alpha-KTx domain in the loop preceding the inner helix, but that the BK turret comprises a unique alpha-KTx interaction surface that likely contributes to the exclusive selectivity of BK channels for alpha-KTx1.x toxins.

P.1.c.028 Role of different types of potassium channels in the antidepressant-like effect of agmatine in the forced swimming test

P.1.c.028 Role of different types of potassium channels in the antidepressant-like effect of agmatine in the forced swimming test

Role of different types of potassium channels in the antidepressant-like effect of agmatine in the mouse forced swimming test

The administration of agmatine elicits an antidepressant-like effect in the mouse forced swimming test by a mechanism dependent on the inhibition of the NMDA receptors and the l-arginine-nitric oxide (NO) pathway. Since it has been reported that the NO can activate different types of potassium (K +) channels in several tissues, the present study investigates the possibility of synergistic interactions between different types of K + channel inhibitors and agmatine in the forced swimming test. Treatment of mice by i.c.v. route with subeffective doses of tetraethylammonium (a non specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channels inhibitor, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K + channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site), augmented the effect of agmatine (0.001 mg/kg, i.p.) in the forced swimming test. Furthermore, the administration of agmatine and the K + channel inhibitors, alone or in combination, did not affect locomotion in the open-field test. Moreover, the reduction in the immobility time elicited by an active dose of agmatine (10 mg/kg, i.p.) in the forced swimming test was prevented by the pre-treatment of mice with the K + channel openers cromakalim (10 μg/site, i.c.v.) and minoxidil (10 μg/site, i.c.v.), without affecting locomotion. Together these data raise the possibility that the antidepressant-like effect of agmatine in the forced swimming test is related to its modulatory effects on neuronal excitability, via inhibition of K + channels.

The inhibition of different types of potassium channels underlies the antidepressant-like effect of adenosine in the mouse forced swimming test

It was previously shown that the acute administration of adenosine elicits an antidepressant-like effect in the mouse forced swimming test (FST) by a mechanism dependent on the inhibition of the l-arginine-nitric oxide (NO)-guanylate cyclase pathway. Taken into account that the stimulation of this pathway is associated with the activation of K + channels, this study investigated the involvement of different types of K + channels in the effect of adenosine in the FST. Intracerebroventricular treatment of mice with tetraethylammonium (TEA, a non-specific inhibitor of K + channels, 25 pg/site), glibenclamide (an ATP-sensitive K + channel inhibitor, 0.5 pg/site), charybdotoxin (a large- and intermediate-conductance calcium-activated K + channel inhibitor, 25 pg/site) or apamin (a small-conductance calcium-activated K + channel inhibitor, 10 pg/site) was able to potentiate the action of subeffective doses of adenosine (1 mg/kg, i.p.) and fluoxetine (a serotonin reuptake inhibitor, 10 mg/kg, i.p.). Furthermore, the administration of adenosine or fluoxetine and the K + channel inhibitors, alone or in combination, did not affect the ambulatory behavior. Moreover, the reduction in the immobility time elicited by active doses of adenosine (10 mg/kg, i.p.) or fluoxetine (32 mg/kg, i.p.) in the FST was prevented by the pretreatment of mice with cromakalim (a K + channel opener, 10 μg/site, i.c.v.), without affecting the locomotion in an open-field. Together these results indicate that the modulatory effects of adenosine and fluoxetine on neuronal excitability, via inhibition of K + channels, may represent the final pathway of their antidepressant-like effects in the FST.

P.2.d.023 Different types of potassium channels underlie the antidepressant-like effect of adenosine in the mouse forced swimming test

P.2.d.023 Different types of potassium channels underlie the antidepressant-like effect of adenosine in the mouse forced swimming test

Different types of potassium channels underlie the long afterhyperpolarization in guinea-pig sympathetic and enteric neurons

Ca 2+-activated K + channels play an important role in the control of neuronal excitability via the generation of the afterhyperpolarization. While both small and large conductance Ca 2+-activated K + channels underlie afterhyperpolarizations in different neuron types, the role of intermediate conductance Ca 2+-activated K + channels (IK Ca) in the generation of afterhyperpolarizations remains unclear. The effects of blockade of IK Ca on guinea pig coeliac and ileal myenteric neurons were studied using single microelectrode current and voltage clamp. In coeliac neurons, TRAM-39, a selective blocker of IK Ca, depressed the amplitude of the prolonged conductance underlying the slow afterhyperpolarization, (gKCa2) by 57%. In contrast, the conductance underlying the prolonged afterhyperpolarization in AH-type myenteric neurons was unaffected by TRAM-39, although it has been suggested that this AHP is mediated by IK Ca. In both types of neurons, TRAM-39 did not alter the resting cell properties or the properties of the action potential. TRAM-39 had no effect on the amplitude of the fast component of the afterhyperpolarization present in sympathetic LAH neurons. The results of this study suggest that in sympathetic LAH neurons, activation of IK Ca underlies at least part of the prolonged afterhyperpolarization while the nature of the channel underlying the AHP in enteric neurons remains unclear.

In Memoriam

HomeCirculation ResearchVol. 94, No. 9In Memoriam Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBIn MemoriamBurton Horowitz Joseph R. Hume and Mark T. Nelson Joseph R. HumeJoseph R. Hume From the Department of Pharmacology, University of Nevada School of Medicine, Reno (J.R.H.); and the Department of Pharmacology, University of Vermont, Burlington (M.T.N). Search for more papers by this author and Mark T. NelsonMark T. Nelson From the Department of Pharmacology, University of Nevada School of Medicine, Reno (J.R.H.); and the Department of Pharmacology, University of Vermont, Burlington (M.T.N). Search for more papers by this author Originally published14 May 2004https://doi.org/10.1161/01.RES.0000130083.96072.92Circulation Research. 2004;94:1151Burt Horowitz, close friend, colleague, and valued collaborator of many in the fields of smooth muscle, vascular, and cardiac research, died prematurely at the age of 48 on December 19, 2003. Dr Horowitz was Professor of Physiology & Cell Biology at the University of Nevada School of Medicine (UNSOM) and was a former member of the Circulation Research Editorial Board. He was internationally recognized for his pioneering research on the molecular biology of ion channels in smooth muscle and the cardiovascular system. Burt is survived by his wife, Nancy, and their two beloved daughters, Claire and Stephanie.Dr Horowitz grew up in Brooklyn, New York, and received a BS degree from Rutgers University in 1976 and a MS degree from California State University, Long Beach, in 1980. He earned a PhD in 1985 in molecular biology with Richard Deonier, followed by postdoctoral training with Robert Farley, both at the University of Southern California. He joined the faculty of UNSOM as an Assistant Professor in Physiology and Cell Biology in 1989.At the time of Burt’s move to UNSOM, little was known about the molecular basis of smooth muscle excitability. Smooth muscle cells in different organs exhibit unique excitation–contraction properties that underlie their fundamental differences in function. Burt provided groundbreaking research to elucidate the molecular properties of a variety of different types of ion channels in visceral and vascular smooth muscle. He provided seminal information on the cellular and molecular basis for gastrointestinal rhythmicity, including the roles of different types of potassium channels. His research probed the properties and molecular nature of voltage-dependent potassium channels and inwardly rectifying potassium channels in the regulation of vascular smooth muscle function.Burt made innumerable research contributions in heart as well. In the early 1990s, he cloned the first chloride channel protein from heart, which he demonstrated was due to cardiac expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. He later identified novel molecular candidates responsible for cell volume-regulated and calcium-activated chloride channels in heart. In addition, he provided important new molecular insights into the signaling pathways controlling function of a variety of chloride channel proteins.Burt made enormous contributions to medical and graduate education at UNSOM and served as director of the graduate program in Cellular & Molecular Pharmacology & Physiology from 1995 to 2002. During his short tenure at UNSOM, he trained 6 PhD students and 11 postdoctoral fellows. In addition, he was an avid organizer of fundraising activities for the Nevada Affiliate of the American Heart Association and was a former director of the Association’s Research Committee. He even managed to find time to develop a pretty good game of golf.Beyond his considerable contributions to smooth muscle and cardiac biology, Burt was a tremendous colleague and collaborator. Burt’s outgoing, insightful, and generous nature was the fuel and energy for a number of very productive collaborations within UNSOM and throughout the country and world. This is the hallmark of a great scientist.“Burt, we’ll meet again, don’t know where, don’t know when… ”Download figureDownload PowerPointThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Dr Joseph R. Hume, Department of Pharmacology/318, University of Nevada School of Medicine, Reno, NV 89557. E-mail [email protected] Previous Back to top Next FiguresReferencesRelatedDetails May 14, 2004Vol 94, Issue 9 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000130083.96072.92 Originally publishedMay 14, 2004 PDF download Advertisement

Anticonvulsant phenytoin affects voltage-gated potassium currents in cerebellar granule cells

The anticonvulsant drug phenytoin (diphenylhydantoin, DPH) was examined for its action on potassium currents in cerebellar granule cells using the whole-cell patch-clamp technique. Granular cells expressed two main types of voltage-dependent potassium currents: the first, sensitive to Tetraethylammonium ion (TEA), resembles a delayed rectifier K + channel ( I d); the second shows biophysical and pharmacological properties similar to an I A-type potassium current. Phenytoin blocks the I A current in a dose-dependent manner, with an apparent dissociation constant K d of (73±7) μM. The drug shifts the steady-state inactivation curves towards a more negative potential, stabilizing the inactivated state, while the activation kinetics remain unaffected. The estimated K d when the cell is held to −100 mV (closed state of the channel) is 145±8 μM which decreases to 35±10 μM at −80 mV holding potential (partial inactivation of the channel). Phenytoin shows a discriminant behaviour between the two different types of potassium channels because at high concentration the effect of the drug on the delayed rectifier K + channel is negligible.