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PubMed2005

Ankyrin-based cardiac arrhythmias: a new class of channelopathies due to loss of cellular targeting.

PURPOSE OF REVIEW: This review addresses a new mechanism for arrhythmia due to abnormal cellular localization of membrane ion channels and transporters. The focus is on ankyrins, a family of proteins that localize diverse membrane ion channels and transporters, and recent evidence that mutations affecting functions of ankyrins result in cardiac arrhythmia. RECENT FINDINGS: A loss-of-function mutation of ankyrin-B in humans and a null mutation in mice result in a dominantly-inherited fatal cardiac arrhythmia initially classified as type 4 long QT syndrome. Characterization of additional probands suggests ankyrin-B mutations cause a new cardiac arrhythmia syndrome associated with sinus node dysfunction that is distinct from long QT syndrome. Ankyrin-B mutation results in elevated calcium transients in cardiomyocytes accompanied by loss of cellular targeting of Na/K ATPase, Na/Ca exchanger, and InsP3 receptor (all ankyrin-binding proteins) to cardiomyocyte membrane domains. The principal voltage-gated Na channel in heart, Nav1.5, is directly associated with ankyrin-G, which is encoded by a distinct gene from ankyrin-B. Mutation of Nav1.5 causing loss of binding to ankyrin-G results in Brugada syndrome and loss of targeting of Nav1.5 to the cell surface of cardiomyocytes. SUMMARY: Ankyrin-B and ankyrin-G are recently recognized constituents of the heart that target diverse ion channels/pumps/transporters to physiologic sites of action in cardiomyocytes. Mutations of ankyrin-B cause a newly defined cardiac arrhythmia syndrome associated with abnormal calcium homeostasis in a mouse model. Ankyrin-G associates with the principal voltage-gated Na channel in the heart, and loss of this interaction due to mutation of Nav1.5 results in Brugada syndrome.

Animals↗
PubMed1995

Mutant mice lacking the gamma isoform of protein kinase C show decreased behavioral actions of ethanol and altered function of gamma-aminobutyrate type A receptors.

Calcium/phospholipid-dependent protein kinase (protein kinase C, PKC) has been suggested to play a role in the sensitivity of gamma-aminobutyrate type A (GABAA) receptors to ethanol. We tested a line of null mutant mice that lacks the gamma isoform of PKC (PKC gamma) to determine the role of this brain-specific isoenzyme in ethanol sensitivity. We found that the mutation reduced the amount of PKC gamma immunoreactivity in cerebellum to undetectable levels without altering the levels of the alpha, beta I, or beta II isoforms of PKC. The mutant mice display reduced sensitivity to the effects of ethanol on loss of righting reflex and hypothermia but show normal responses to flunitrazepam or pentobarbital. Likewise, GABAA receptor function of isolated brain membranes showed that the mutation abolished the action of ethanol but did not alter actions of flunitrazepam or pentobarbital. These studies show the unique interactions of ethanol with GABAA receptors and suggest protein kinase isoenzymes as possible determinants of genetic differences in response to ethanol.

Animals↗
PubMed1993

Sperm competition games: sperm size and number under gametic control.

This paper examines sperm competition games in which both size and number of gametes in an ejaculate can be varied strategically, but under the control of the haploid sperm. It is a companion to the previous paper (Parker (Proc. R. Soc. Lond. B 253, 245 (1993))) for the case where the strategic control is by the diploid parent. Under haploid control, the optimal balance between size and number of sperm in an ejaculate becomes quite different from that predicted for diploid control; there is a conflict between parental and gametic interests over sperm size and number. This occurs because both intra-ejaculate and inter-ejaculate sperm competition are present with haploid control, whereas intra-ejaculate competition is absent under diploid control. The magnitude of this conflict is affected by the risk of inter-ejaculate sperm competition, and by the fact that gametic interests depend on the nature of available mutations. If ejaculate expenditure trades off against numbers of matings achieved, with haploid control there is escalation towards maximal expenditure on the ejaculate. If the ejaculate expenditure is fixed by the diploid parent, but there is a size-number trade-off under haploid control, solutions depend on the mode of action of the mutation affecting sperm size or number. If mutant-bearing sperm deviate entirely at the expense of non-mutant sperm, any increase in size or number will spread. If mutant sperm deviate entirely at their own expense, the evolutionarily stable strategy (ESS) is the same as for diploid control; there is no conflict.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1970

Patterned neural activity of a mutant Drosophila melanogaster.

Hyperkinetic (1P), a behavioral mutant of Drosophila melanogaster, shows rhythmic leg-shaking action derived from mutation of a single, sex-linked gene. The neural mechanism governing this abnormal motor function consists of rhythmic bursts of activity produced by motor neurons located within the thoracic ganglion. The mechanism of the pattern formation was independent both of sensory information and higher centers in the central nervous system but endogenous within the ganglion. Two types of neurons which appear to be involved in the pattern formation were found within six limited regions.

Action Potentials↗
PubMed2001

Presenilin mutations and calcium signaling defects in the nervous and immune systems.

Presenilin-1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early-onset inherited forms of Alzheimer's disease (AD) by a gain-of-function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid beta-peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic reticulum (ER) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems.

Alzheimer Disease↗
PubMed2005

A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs.

Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I(Na)). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the beta1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.

Adult↗
PubMedDate not supplied

[The characteristics of the expression of temperature-dependent dominant lethal mutations in Drosophila melanogaster].

The results of a series of investigations on obtaining and analysing dominant temperature-sensitive lethals (DTS-lethals) are summarized. Using EMS, both cold- and heat sensitive mutations of this type were induced in large autosomes. The cold-sensitive mutations of chromosome 3 were revealed for the first time. The effect of genetic phone on DTS lethal penetrance and expressivity was studied. The character of expression of two mutations possessing a pleiotropic action was examined. The heat-sensitive 1(2)M90DTS mutation disturbed the structure of abdominal tergites in all imago and, besides, caused an abrupt decrease in the female reproductive period. The pattern of alterations observed in oogenesis along with the result of phenogenetic analysis suggest that this gene takes part in the genetic control over the proliferation of stem oogonial cells. The cold-sensitive 1(2)M66DCS mutation caused a number of disturbances in imago thoracic structures: inability to flight, raised up wings, extremity fracture, etc. Mutant flies showed serious disorders of indirect flight muscles both at morphological and at ultrastructural levels. It was established that this mutation was a cold-sensitive allele of Mhc gene which controls the synthesis of myosine heavy chains in drosophila.

Alleles↗
PubMed2001

Cholesterol mobilization by free and lipid-bound apoAI(Milano) and apoAI(Milano)-apoAII heterodimers.

Despite very low plasma levels of HDL, carriers of the apolipoprotein AI Arg173 --> Cys mutation apoAI(Milano) (AIM) have no apparent increase in risk for atherosclerotic vascular disease. HDL apolipoprotein species in AIM carriers include apoAI-AII heterodimers, previously found to confer the enhanced ability of tyrosyl radical-oxidized HDL to mobilize cholesterol for removal from cultured cells. To determine whether enhanced mobilization of cholesterol by apoprotein species in AIM explains a cardioprotective action of this mutation, we examined the ability of lipid-free and lipid-bound AIM and AIM-AII heterodimers to deplete cholesterol from cultured cells. Free AIM and AIM-AII heterodimers showed a decreased capacity to act as acceptors of cholesterol from cholesterol-loaded human fibroblasts compared with native apoAI but similar capacities to deplete fibroblasts of the pool of cholesterol available for esterification by acyl-CoA:cholesterol acyltransferase (ACAT). Discoidal reconstituted HDL (rHDL) containing apoAI depleted both of these cholesterol pools more readily than AIM-containing rHDL when compared at equivalent rHDL protein levels, but similar abilities of these rHDL to deplete cell cholesterol were seen when compared at equivalent phospholipid levels. Spherical rHDL generated using the whole lipid fraction of HDL and apoAI or AIM showed similar capacities to deplete total and ACAT-accessible cell cholesterol when compared at similar protein levels, but an increased capacity of AIM-containing particles was seen when compared at equivalent phospholipid levels. Unlike the apoAI-AII heterodimer in tyrosylated HDL, AIM-AII heterodimer-containing spherical rHDL showed no increased capacity to deplete either of these pools of cholesterol. These results suggest a similar or better capacity of native apoAI in lipid-free or lipid-bound form in discoidal rHDL to enhance the mobilization of cellular cholesterol when compared to AIM in its free or lipid-bound forms. Any increase in depletion of cellular cholesterol by lipid-bound AIM in spherical rHDL appears related to altered phospholipid-binding rather than intrinsic cholesterol-mobilizing characteristics of this protein compared to native apoAI. The lack of major differences in these studies in cholesterol mobilization by native apoAI and AIM, or by apoAIM-AII heterodimers, suggests that any protection against atherosclerosis conferred by this mutation is likely related to other beneficial vascular effects of AIM.

Apolipoprotein A-I↗
PubMed1997

Mutational study of the amino-terminal domain of human tissue inhibitor of metalloproteinases 1 (TIMP-1) locates an inhibitory region for matrix metalloproteinases.

A bacterial expression system for the inhibitory N-terminal domain of human tissue inhibitor of metalloproteinases 1 (N-TIMP-1) (Huang, W., Suzuki, K., Nagase, H., Arumugam, S., Van Doren, S. R., and Brew, K. (1996) FEBS Lett. 384, 155-161) has been used to produce 20 single- and double-site mutants that probe the roles of different residues in its inhibitory action on metalloproteinases. Mutations that produce the largest increases in the Ki for a C-terminally truncated form of stromelysin 1, MMP-3(DeltaC), but do not disturb the conformation involve substitutions of residues that are located in a ridge that is centered around the disulfide bond between Cys1 and Cys70. Specific residues that have a large influence on activity include Cys1, Thr2, Met66, Val69, and Cys70. Of the mutations introduced, the greatest functional disturbances, reflected in Ki increases of 2-4 orders of magnitude, are generated by changes that disrupt the Cys1-Cys70 disulfide bond and by substitution of Ala for Thr2. Most mutations that perturb the interaction with MMP-3 have parallel effects on the affinity of N-TIMP-1 for MMP-1 (interstitial collagenase) and MMP-2 (gelatinase A). However, the Thr2 to Ala mutation produces an inhibitor that is 17-fold more effective against MMP-3 than MMP-1, suggesting that it is feasible to engineer TIMP-1 variants that are more specifically targeted to selected matrix metalloproteinases. The reactive site identified by these studies is a structurally constrained but elongated region of TIMP that can fit the matrix metalloproteinase substrate-binding site.

Binding Sites↗
PubMed1999

The effects of a point mutation of the beta2 subunit of GABA(A) receptor on direct and modulatory actions of general anesthetics.

The gamma-aminobutyric acid type A receptor (GABA(A) receptor) sites involved in the direct and modulatory actions of general anesthetics remain to be elucidated. The mutation of tyrosine at position 157 in the beta2 GABA(A) receptor subunit was reported to reduce sensitivity to activation by GABA, but not pentobarbital. We examined whether this mutation of the beta2 subunit (Tyr157-->Phe) affects the direct and modulatory actions of other general anesthetics such as propofol and etomidate. Using the two-electrode voltage clamp method, we recorded Cl- current in Xenopus oocytes expressing alpha1beta2gamma2s and alpha1-mutated beta2gamma2s subunits. The mutation of the beta2 subunit reduced the apparent affinity for propofol. However, the mutation had no effect on both the direct actions of pentobarbital and etomidate or on the modulatory actions of pentobarbital, propofol and etomidate. These results suggest that unique loci may exist for the direct action of propofol and that the GABA binding site may not mediate the modulatory actions of general anesthetics at GABA(A) receptors.

Amino Acid Substitution↗
PubMed1996

Distinct effects of mutations in transmembrane segment IVS6 on block of L-type calcium channels by structurally similar phenylalkylamines.

The phenylalkylamines (-)-D888, verapamil, and D600, cause voltage- and use-dependent block of L-type Ca2+ channels and differ from each other only in the number of methoxy groups on each of their two terminal phenyl rings. To study the effects of mutations in the phenylalkylamine receptor site on block by these drugs, wild-type and mutant Ca2+ channels were transiently expressed in the tsA-201 clone of human embryonic kidney 293 cells. The combined mutations Y1463A, A1467S, and I1470A (mutant YAI) in transmembrane segment S6 of domain IV of the alpha 1c subunit disrupted block by all three phenylalkylamines. Surprisingly, although this mutation reduced both resting block at -60 mV and depolarized block at +10 mV by (-)-D888, resting and depolarized block by verapamil and D600 were relatively unaffected. In contrast, for all three drugs, use-dependent block during repetitive stimulations was sharply reduced, and the rate of recovery from depolarized block was accelerated for YAI channels. Thus, the effects of the YAI mutation on apparent affinity were specific to (-)-D888, whereas effects on the kinetics of block were observed for all three drugs. Additional experiments with substitution of phenylalanine for Y1463 suggested that (-)-D888 affinity is specifically sensitive to removal of the hydroxyl group of Y1463, whereas effects on the kinetics of block by all three phenylalkylamines require larger molecular changes, perhaps related to residue size and hydrophobicity. Analysis of the data using a state-dependent model of drug block suggests that these kinetic differences are caused by both changes in drug access to the receptor site and affinity for binding to the inactivated state of the channel. The different effects of the YAI mutations on the actions of (-)-D888, verapamil, and D600 indicate that these residues interact differently with these closely related drugs.

Amino Acid Sequence↗
PubMed1999

The thyroid hormone receptor-beta gene mutation R383H is associated with isolated central resistance to thyroid hormone.

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of TRH from the hypothalamus and of TSH from the anterior pituitary despite elevated levels of thyroid hormone (T4 and T3). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-beta. Most individuals with TR-beta mutations have generalized resistance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation. Whether TR-beta mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received three escalating T3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal TR exons were sequenced revealing the mutation R383H in a region not otherwise known to harbor TR-beta mutations. Our clinical evaluation presented here represents the most thorough documentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-beta mutation.

Body Weight↗
PubMed1992

The distribution of spontaneous mutations on quantitative traits and fitness in Drosophila melanogaster.

Starting from a completely homozygous population of Drosophila melanogaster, two groups of 100 inbred lines each were established and maintained for 46 generations, by a single brother-sister mating and two double first cousin matings, respectively. Sternopleural bristle number, wing length and wing width were simultaneously scored in all lines every 4-5 generations. The means of four lines in each group departed significantly from the overall mean and, in each case, this was attributed to a single mutation of relatively large effect on at least one trait (0.3-1.4 environmental standard deviations in absolute value). Further analyses revealed widespread pleiotropy, similar gene action of a given mutation for all traits affected, and predominant additive action. No apparent association was found between the magnitudes of mutational effects on the traits and fitness. However, all recessive mutations were deleterious. The distribution of mutant effects was asymmetrical (positive for bristles and negative for wing measurements). Moreover, these distributions had a high variance and may be leptokurtic, due to the presence of major genes. Estimates of the ratio of new mutational variance to environmental variance ranged within (0.7-3.4) x 10(-3), those for wing measurements being generally larger. In agreement with theory, the rate of between-line differentiation was independent of population size.

Animals↗
PubMed1997

The bacterial outer membrane as a drug barrier.

The outer membranes of Gram-negative bacteria constitute a semi-permeable barrier, as indicated by the corresponding alterations in outer membrane permeability and in antibiotic susceptibility resulting from mutation or polycation action. Restricted outer membrane permeability works in synergy with co-determinant resistance mechanisms, such as the periplasmic enzyme beta-lactamase or active efflux mechanisms, bringing about antibiotic resistance.

Anti-Bacterial Agents↗
PubMed1969

Mutations to spectinomycin resistance which alleviate the restriction of an amber suppressor by streptomycin resistance.

Unlike mutations to streptomycin resistance, which restrict the function of an SU II amber suppressor, mutations to spectinomycin resistance have no restrictive effect. Furthermore, mutations to spectinomycin resistance counteract the restrictive action of streptomycin-resistant mutations when combined in a single strain. The mutations to drug resistance, singly or in combination, do not themselves lead to any detectable suppressor activity. The effects on SU II are interpreted in terms of interactions between ribosomal elements.

Coliphages↗
PubMed2005

Autonomic control of cardiac action potentials: role of potassium channel kinetics in response to sympathetic stimulation.

I(Ks), the slowly activating component of the delayed rectifier current, plays a major role in repolarization of the cardiac action potential (AP). Genetic mutations in the alpha- (KCNQ1) and beta- (KCNE1) subunits of I(Ks) underlie Long QT Syndrome type 1 and 5 (LQT-1 and LQT-5), respectively, and predispose carriers to the development of polymorphic ventricular arrhythmias and sudden cardiac death. beta-adrenergic stimulation increases I(Ks) and results in rate dependent AP shortening, a control system that can be disrupted by some mutations linked to LQT-1 and LQT-5. The mechanisms by which I(Ks) regulates action potential duration (APD) during beta-adrenergic stimulation at different heart rates are not known, nor are the consequences of mutation induced disruption of this regulation. Here we develop a complementary experimental and theoretical approach to address these questions. We reconstituted I(Ks) in CHO cells (ie, KCNQ1 coexpressed with KCNE1 and the adaptator protein Yotiao) and quantitatively examined the effects of beta-adrenergic stimulation on channel kinetics. We then developed theoretical models of I(Ks) in the absence and presence of beta-adrenergic stimulation. We simulated the effects of sympathetic stimulation on channel activation (speeding) and deactivation (slowing) kinetics on the whole cell action potential under different pacing conditions. The model suggests these kinetic effects are critically important in rate-dependent control of action potential duration. We also investigate the effects of two LQT-5 mutations that alter kinetics and impair sympathetic stimulation of I(Ks) and show the likely mechanism by which they lead to tachyarrhythmias and indicate a distinct role of I(KS) kinetics in this electrical dysfunction. The full text of this article is available online at http://circres.ahajournals.org.

A Kinase Anchor Proteins↗
PubMed2002

Effects of mutations at the two processing sites of the precursor for the small subunit of ribulose-bisphosphate carboxylase in Chlamydomonas reinhardtii.

The role of the two processing sites in the precursor of the small subunit (SS) of ribulose-1,5-bisphosphate carboxylase/oxygenase (pSS) of Chlamydomonas reinhardtii was studied by introducing mutations at the cleavage sites for the stromal processing peptidases SPP-1 and SPP-2, which hydrolyse wild-type pSS (20.6 kDa) to an intermediate-sized product iSS (18.3 kDa) and to the mature SS (16.3 kDa), respectively. The mutations introduced into cDNA resulted in exchange of (a) two amino acids flanking processing site 1, or (b) one or (c) both amino acids flanking processing site 2. Mutation (a) prevented pSS from being processed at site 1 but not from cleavage at site 2. Mutation (c) abolished the action of SPP-2 but not SPP-1. When pSS with mutation (c) was imported into isolated chloroplasts, iSS accumulated while SS formation was abolished. However, mature SS was produced even in the absence of iSS synthesis (mutation a). Import of pSS bearing mutation (b), which only partially inhibited processing at the SPP-2 site, slowed the rate of SS formation down whereas iSS and some slightly smaller derivatives accumulated. These experiments suggested that in Chlamydomonas processing of pSS can occur in two steps, whereby the first step is facultative. The same three mutations were studied in vivo after transformation of SS-deficient C. reinhardtii T60-3 with mutated genomic DNA. Growth and photosynthesis was as in control transformants, except for the slower-growing transformants (mutation c) where no mature SS was immuno-detected. However, pSS fragments with molecular masses between those of iSS and SS were present even in the ribulose-1,5-bisphosphate carboxylase/oxygenase holoenzyme.

Animals↗