Das sog. Endokardmyxom

Summary Three cardiac Myxomas were studied by light-, immuno-fluorescence and electron microscopy. Acid mucopolysaccharides of the tumour were isolated chromatographically. The surfaces of the myxomas were papillary in two cases and smooth in one. The smooth surfaced tumour recurred six months after primary resection; histological specimens were more cellular than those of the papillary tumors and showed nuclear polymorphism and mitoses. The cells of two papillary tumours were identified as endocardial by electron microscopy, however, the cells of the smooth surfaced tumour were typical myofibroblasts. In both types of myxomas the cells were rich on cytoplasmic filament that contained acto-myosin. Biochemical investigation failed to reveal any difference between the acid mucopolysaccharide pattern of the two tumour types; isolated mucopolysaccharides being typical for embryonal mesenchymal tissue.The authors agree with Albertini (1963), that cardiac myxoma is a misnomer for two different typical endocardial tumours: a true endothelioma and a special fibroma (myofibroma or myofibrosarcoma).

     

Lability in the responses of cells in the auditory cortex of squirrel monkeys to species-specific vocalizations

Summary The activity of 28 cells located mainly in the secondary auditory cortex (A II) of awake squirrel-monkeys, was extracellularly recorded for periods of up to 6 h. Seven different species-specific vocalizations, which were repeatedly presented to the monkey, were used as auditory stimuli. Twenty-six cells responded, at least once, to one or more vocalizations; 22 cells revealed some change in their response (pattern or strength) to at least one vocalization (change in response). Twenty-one cells exhibited a change in the number and/or type of vocalization to which they responded during the recording period (change in selectivity). At some time during the recording period all the responding cells exhibited a change in response and/or a change in selectivity (change in responsiveness). A change in response of a cell to a vocalization did not necessarily exclude a change in selectivity, associated with the same vocalization, later in time and vice-versa. A change in responsiveness to one vocalization was not necessarily correlated with changes in responsiveness to other vocalizations.     

Farmerlunge

Ohne ZusammenfassungAus den Laboratorien der Marshfield Clinic und Marshfield Clinic Foundation for Medical Research and Education, Marshfield, Wisconsin, USA. Die Arbeit wurde durchgeführt mit Unterstützung des US Public Health Service, Bewilligungsnummer UI-00398.Die Autoren sind Dr.Dieter M. Voss für seine wertvolle Hilfe bei der Vorbereitung des Manuskriptes zu Dank verpflichtet.Deutsche Übersetzung: Dr.M. v. Bubnoff, München.     

Endothelial cilia in human aortic atherosclerotic lesions

Summary Primary cilia were present in the endothelial cells of human aortic fatty dots and streaks but not in those of normal intima. They had the features of cilia of the 9+0 axonemal configuration observed in many other cells. A lateral foot process and transitional fibers anchored the ciliary basal body in the cytoplasm, but rootlets were not identified in material examined. Ladder-like configurations interconnected the two centrioles (=diplosome) of control endothelium.The primary cilia of endothelium differed from those of the rudimentary type observed in smooth muscle cells in similar lesions of man, but shared many features with cilia of those present in experimental atherosclerosis in rabbit.Cilia were rarely described in vascular endothelium. It is believed that, to date, they were not reported to occur in normal or pathological arteries in man.It is being stressed that whereas the significance of these unusual organelles remains uncertain, their widespread occurrence may indicate that their role is more important than was believed previously, and they should cease being a curiosity only.Presented-in-part at the Workshop of the American Heart Association: Evolution of the Human Atherosclerotic Plaque, Rockville, Maryland, September 20–23, 1986.Dedicated to Professor Dr. Gotthard Schettler, Department of Internal Medicine, University of Heidelberg, FRG, on the occasion of his 60 birthday (April, 1987).     

Is there a retinopetal system in the rat?

Summary The centrifugal innervation of the retina was reinvestigated in albino and pigmented rats with intraocular injections of horseradish peroxidase (HRP), radioactive wheat germ agglutinin (WGA) and proline. No labeled cells were found in the brains injected with HRP and proline, except some eye muscle motoneurons in one case apparently involving orbital contamination from the injection. In the cases injected with WGA and having a survival time of at least two days cells were labeled in the lateral mesencephalic tegmentum, ventral to the parabigeminal nucleus and in the periaqueductal gray. Both these findings are most likely due to transneuronal anterograde-retrograde transport of the tracer through the superior colliculus. The results yielded no compelling evidence for the existence of a direct retinopetal pathway in the rat, which is in contrast to a recently claimed retinal projection originating from the pretectum. Special attention was paid to the labeling in the lateral mesencephalic tegmentum, an area giving rise to retinal projections in various submammalian species. This finding is discussed with regard to the possibility that also in the rat the lateral tegmentum exerts an early influence on visual input, but at the higher collicular level and not at the original retinal one.Supported by the Swiss National Science Foundation (grants no. 3.433.78, 3.505.79 and 3.580.79), the EMDO-Stiftung and the Dr. Eric Slack-Gyr-Stiftung in Zürich     

Synergistic effects of tumour necrosis factor-α and interferon-γ on feline haemopoietic progenitors

Pathogenic mechanisms that underlie feline leukaemia virus subgroup-C (FeLV-C) induced erythroid aplasia are unknown. FeLV-C infection is associated with higher serum levels of interferon- (IFN-) and tumour necrosis factor- (TNF-), which may act synergistically to cause haemopoietic suppression. In the present studies, the synergistic effects of TNF- and IFN- on feline bone marrow progenitors in vitro were evaluated. Bone marrow mononuclear cells from specific-pathogen-free cats were exposed to TNF- (100 and 200 pg/ml) and IFN- (100 or 200 units/ml), alone or in combination, for 2 h before plating for clonal assays of colony forming units. Our results show that TNF- and IFN- in combination caused marked suppression of feline colony forming units-erythroid (CFU-E), burst forming units-erythroid (BFU-E), and colony forming units-fibroblasts (CFU-F), whereas colony forming units-granulocyte/macrophage (CFU-GM) were minimally affected. The same concentrations of TNF- and IFN- alone had minimal effects on CFU-E, BFU-E and CFU-F. These results suggest that TNF- and IFN- may play a significant role in regulating haemopoiesis in cats and may be involved in the pathogenesis of erythroid aplasia in cats infected with feline leukaemia virus.     

Firing characteristics of vestibular nuclei neurons in the alert monkey after bilateral vestibular neurectomy

Summary After destruction of the peripheral vestibular system which is not activated by moving large-field visual stimulation, not only labyrinthine-ocular reflexes but also optokinetic-ocular responses related to the velocity storage mechanism are abolished. In the normal monkey optokinetic-ocular responses are reflected in sustained activity changes of central vestibular neurons within the vestibular nuclei. To account for the loss of optokinetic responses after labyrinthectomy, inactivation of central vestibular neurons consequent on the loss of primary vestibular activity is assumed to be of major importance. To test this hypothesis we recorded the neural activity within the vestibular nuclear complex in two chronically prepared Rhesus monkeys during a period from one up to 9 and 12 months after both vestibular nerves had been cut. The discharge characteristics of 829 cells were studied in relation to eye fixation, and to a moving small and large (optokinetic) visual stimulus producing smooth pursuit (SP) eye movements and optokinetic nystagmus (OKN). Units were grouped into different subclasses.After chronic bilateral vestibular neurectomy (BVN) we have found: (1) a rich variety of spontaneously active cells within the vestibular nuclear complex, which — as far as comparison before and after BVN is possible — belong to all subclasses of neurons functionally defined in normal monkey; and (2) no sustained activity changes which are related to the activation of the velocity storage mechanism; this is especially true for pure-vestibular, vestibular-pause and tonic-vestibular-pause cells in normal monkey which show a pure, pause and tonic-pause firing pattern after BVN. Neurons which are modulated by eye position are, however, modulated with the velocity of slow eye movements with comparable sensitivity during SP and OKN. Retinal slip is extremely rarely encoded. The results of the present study do not directly answer the question why the velocity storage mechanism is abolished after BVN but they suggest that only a small number of central vestibular cells may be inactivated by neurectomy.Supported by SNF grant no. 3.510-0.86     

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express α1, α3 and α5 chains of β1 integrins

The expression of the 1 integrins was examined immunohistochemically in synoviocytes from normal synovial membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were 61-positive but lacked 1 through 5. In mild inflammation type A synoviocytes neo-expressed 1, 3, and 5 chains. In severe inflammation both type A and B synoviocytes expressed 3, 4, 5, and 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 (IL-1), tumour necrosis factor- (TNF-), and interferon- (INF-). This effect was enhanced by combining IL-1 and TNF-. Expression of the 3 chain was up-regulated by IL-1 and, more intensely, by IFN-. Transforming growth factor (TGF-) inhibited the up-regulating effect of IL-1 and antagonized the effect of IFN- on 3 chain expression. Expression of the 5 chain was up-regulated significantly by co-stimulation through IL-1 together with TGF- or TNF-. Thus, the 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1, TNF-, IFN-, and TGF- are likely to be among the effectors regulating 1 integrin expression in synoviocytes in vivo.     

Inhibition of the M current in NG108-15 neuroblastoma × glioma hybrid cells

The M current, I _M, a voltage-dependent non-inactivating K current, was recorded in NG108-15 neuroblastoma × glioma hybrid cells, using the whole-cell mode of the patch-clamp technique. We studied inhibition of the M current by bradykinin, phorbol dibutyrate (PDBu), an activator of protein kinase C (PKC), and methylxanthines. Focal application of 0.1–5 M bradykinin inhibited I _M by about 60%; 5 nM bradykinin inhibited by about 40%. Bath application of 0.1 M and 1 M PDBu diminished I _M to about half of the control value. Staurosporine, a PKC inhibitor, applied for 35–43 min in a concentration of 0.3 M significantly reduced the effect of 1 M PDBu. M current blockage by PDBu could be partly reversed by bath application of H-7 (51–64 M), another PKC inhibitor. These observations suggest that the PDBu effect is really due to activation of PKC. The findings are compatible with the view [Brown DA, Higashida H (1988) J Physiol (Lond) 397:185–207] that the bradykinin effect on I _M is mediated by PKC. However, three further observations suggest that this is only true for part of the bradykinin effect. When the suppression of I _M by 1 M PDBu was fully developed, 0.1 M bradykinin produced a further inhibition of I _M. Down-regulation of PKC by long-term treatment with PDBu reduced the effect of 0.1 M bradykinin significantly but did not abolish it. Staurosporine (0.3 M, applied for 31–46 min) failed to reduce the effect of 5 nM bradykinin significantly. The M current could be reversibly blocked by methylxanthines (caffeine, isobutylmethylxanthine, theophylline) in the millimolar range, probably because of a direct action on the M channels.     

Spatial auditory attention is modulated by tactile priming

Previous studies have shown that cross-modal processing affects perception at a variety of neuronal levels. In this study, event-related brain responses were recorded via whole-head magnetoencephalography (MEG). Spatial auditory attention was directed via tactile pre-cues (primes) to one of four locations in the peripersonal space (left and right hand versus face). Auditory stimuli were white noise bursts, convoluted with head-related transfer functions, which ensured spatial perception of the four locations. Tactile primes (200–300 ms prior to acoustic onset) were applied randomly to one of these locations. Attentional load was controlled by three different visual distraction tasks. The auditory P50m (about 50 ms after stimulus onset) showed a significant proximity effect (larger responses to face stimulation as well as a contralaterality effect between side of stimulation and hemisphere). The tactile primes essentially reduced both the P50m and N100m components. However, facial tactile pre-stimulation yielded an enhanced ipsilateral N100m. These results show that earlier responses are mainly governed by exogenous stimulus properties whereas cross-sensory interaction is spatially selective at a later (endogenous) processing stage.This research has been supported by the DaimlerChrysler AG, DARPAs AugCog program, and the German Research Foundation DFG (SFB 550/B1).     

Increase in TCRγδ T lymphocytes in synovia from rheumatoid arthritis patients with active synovitis

To determine the relative presence of TCR+ and TCR+ T cells in synovial tissue from patients with various types of inflammatory synovitis and in tissues from patients with a number of chronic T cell-mediated conditions, we stained frozen tissue sections with monoclonal antibodies in indirect immunofluorescence assays. In tissues obtained from patients with chronic T cell-mediated granulomatous conditions (Wegener's granulomatosis, lymphomatoid granulomatosis, granuloma annulare, Langerhan's cells granulomatosis, pigmented villonodular synovitis, Takayasu's arteritis, and talc granulomatosis), the T cells present were predominantly TCR+, without an increased presence of TCR+ cells. In contrast, 6 of 14 (43%) synovia from patients with rheumatoid arthritis (RA) showed increased TCR+ T cells (3–10 cells/hpf). The RA synovia with increased TCR+ cells present had an increased tissue inflammation score compared to RA synovia with few TCR+ cells [18.6±5.8 versus 11.6±4.2 (mean±SE),P<0.05]. In contrast, synovia from patients with osteoarthritis, systemic lupus erythematosus, and trauma did not show an increased presence of TCR+ T cells. Thus, in cellular inflammatory infiltrates the presence of increased TCR cells is not a component of noninfectious granulomatous inflammation but is found in approximately 40% of RA synovia with high levels of inflammation.     

Specific demonstration of actin and keratin filaments in pleomorphic adenomas by means of immunoelectron microscopy

Summary Human pleomorphic adenomas of the parotid gland were investigated by means of immunocytochemistry. Antibodies against the filaments of the actin and the keratin type were used on the light and electron microscopical level. For the immunoelectron microscopic procedure, the pre-embedding technique was applied. Actin and keratin were demonstrated in tumour cells. These observations provide further informations to the ambiguous nature of these neoplastic cells.Prof. Dr. G. Seifert to his 60th birthdaySupported by the Hamburger Stiftung zur Förderung der Krebsbekämpfung and the Deutsche Forschungsgemeinschaft (Ca 93/1-1, Lo 285/2-1)     

Immunocytochemical characterization of porcine zona pellucida during follicular development

Sections of bovine ovaries fixed in Bouin's fluid or methanol-acetic acid and embedded in paraffin were incubated with chicken polyclonal antibodies to HPLC-purified zona glycoproteins ZP3 and ZP3. Oocytes of primordial follicles as well as of primary follicles showed weak labelling with anti-ZP3 and anti-ZP3. No immunostaining could be observed in the follicle cells. The ZP of primary follicles displayed distinct immunoreactivity for both ZP3 and ZP3. In secondary follicles, distinct labelling with anti-ZP3 and weak labelling with anti-ZP3 could be seen in the oocyte. The ZP showed immunoreactivity with antibodies to ZP3 and ZP3. Both antibodies labelled single follicle cells. In tertiary follicles, the oocytes were weakly labelled with anti-ZP3 and anti-ZP3. Some granulosa cells showed staining for ZP3 and ZP3. The ZP displayed strong immunoreactivity for ZP3 and ZP3. Cells of the corona radiata were strongly immunopositive for ZP3 and ZP3. Similar histotopography of immunoreactive cells could be seen in preovulatory follicles. The characteristic pattern observed for the distribution of ZP3 and ZP3 strongly suggests that in the porcine ovary both the oocyte and the follicle cells contribute to the synthesis of the ZP, perhaps in sequence.     

A Possible Mechanism for the Dopamine-Evoked Synergistic Disinhibition of Thalamic Neurons Via the “Direct” and “Indirect” Pathways in the Basal Ganglia

The mechanism of synaptic plasticity which we have previously proposed for striatal spiny neurons, along with published data on the predominance of dopamine-sensitive D1/D2 receptors on strionigral/striopallidal neurons, was used as the basis to propose the hypothesis that the induction of long-term potentiation/depression of the efficiency of the cortical inputs to these cells may result from the excitatory/inhibitory actions of dopamine on the activity of the neurons originating the direct and indirect pathways through the basal ganglia. Thus, the action of dopamine increases disinhibition of thalamic neurons via the direct pathway and decreases their inhibition via the indirect pathway. Both effects lead to increases in the activity of thalamic cells and in the activity of the efferent neocortical neurons which they excite. The actions of dopamine on striosomal neurons, which mainly have D1 receptors, may also be to induce long-term potentiation of cortical inputs. This effect should lead to increased inhibition of dopaminergic cells and decreases in their dopamine release, which may promote the maintenance of a stable dopamine concentration in the cortex-basal ganglia-thalamus-cortex neural network.     

Immunohistochemical studies on S-100 cells in the anterior pituitary gland of Sprague Dawley rats and spontaneous dwarf rats

The S-100 cells in the pituitary glands of adult male Sprague Dawley rats (SDs) and spontaneous dwarf rats (SDRs) were immunohistochemically examined using anti-S-100 and anti-S-100 monoclonal antibodies. The immunoreactive cells against S-100 protein were divided into three subtypes on the basis of their immunore-activity against subunits of S-100 protein: S-100 dominant type (the -type cell), S-100 dominant type (the \-type cell) and immunoreactive against both S-100 and S-100 (the -type cell). In the SD, -type cells represented 26% of the total S-100 immunoreactive cells (S-100 cells) and were localized in the peripheral area of the ventral region of the pituitary gland. This type of cell was observed forming clusters, with more abundant cytoplasm than the -type cell. The proportion of -type cells was 53%. They were diffusely distributed throughout the gland, and their processes were thicker than those of the -type cell. In the SDR, the proportion of -type cells was 55%, and they were observed throughout the gland. In contrast, -type cells totalled 12% and were localized in small areas of the central and peripheral region of the gland. The proportion of -type cells was 21% in the SD and 33% in the SDR and they were observed forming small clusters in both animal groups. The proportion of -type cells compared with the total of S-100-immunoreactive cells was significantly higher (P < 0.05) in the SDR than in the SD, while the proportion of -type cells was markedly lower (P < 0.05).     

On the regulation of the expressed L-type calcium channel by cAMP-dependent phosphorylation

The Ca²⁺ channel subunits _1C-a and _1C-b were stably expressed in Chinese hamster ovary (CHO) and human embryonic kidney (HEK) 293 cells. The peak Ba²⁺ current (I _Ba) of these cells was not affected significantly by internal dialysis with 0.1 mM cAMP-dependent protein kinase inhibitor peptide (mPKI), 25 M cAMP-dependent protein kinase catalytic subunit (PKA), or a combination of 25 M PKA and 1 M okadaic acid. The activity of the _1C-b channel subunit expressed stably in HEK 293 cells was depressed by 1 M H 89 and was not increased by superfusion with 5 M forskolin plus 20 M isobutylmethylxanthine (IBMX). The _1C-a·₂·₂/ complex was transiently expressed in HEK 293 cells; it was inhibited by internal dialysis of the cells with 1 M H 89, but was not affected by internal dialysis with mPKI, PKA or microcystin. Internal dialysis of cells expressing the _1C-a·₂·₂/ channel with 10 M PKA did not induce facilitation after a 150-ms prepulse to +50 mV. The Ca²⁺ current (I _Ca) of cardiac myocytes increased threefold during internal dialysis with 5 M PKA or 25 M microcystin and during external superfusion with 0.1 M isoproterenol or 5 M forskolin plus 50 M IBMX. These results indicate that the L-type Ca²⁺ channel expressed is not modulated by cAMP-dependent phosphorylation to the same extent as in native cardiac myocytes.     

The role ofγδ T cells in the normal and disordered immune system

Summary A small population of T cells does not express the conventional T cell receptor characterized by the and polypeptide chains (TCR) but instead, two polypeptides termed and (TCR). This alternative receptor is able to recognize antigen. It appears early in T cell ontogeny, but its role in the thymus prior to the availability of TCR remains unclear. In selected sites such as skin or gut TCR predominates in mice which might suggest a role of T cells in the first line of defense against infection, T cells secrete lymphokines and display cytotoxic activity. However, their activation requirements may differ from what is known for T cells since MHC-nonrestricted and also CD4 and CD8 negative T cells have been described. Preferential activation by mycobacterial antigens possibly indicates a special repertoire of the T cells. In various diseases slightly increased numbers of T cells were found, but these preliminary studies have not yet provided evidence for a major pathogenetic role of T cells.List of abbreviations C constant region (immunoglobulin or TCR gene segment) - CD4 cluster of differentiation 4 (mainly on helper cells) - CD8 cluster of differentiation 8 (mainly on cytotoxic cells) - D diversity region (immunoglobulin or TCR gene segment) - DNA desoxyribonucleic acid - IL2 interleukin 2 - J joining region (immunoglobulin or TCR gene segment) - kD kiloDalton - MHC major histocompatibility complex - NK natural killer (cells) - RA rheumatoid arthritis - TCR T cell receptor - V variable region (immunoglobulin or TCR gene segment)     

Zur Polypeptidketten-Struktur von Immunglobulinen

Zusammenfassung Die Ergebnisse optischer Drehfähigkeitsmessungen an H- und L-Polypeptidketten normaler und Myelomproteine vom G-Typ werden mitgeteilt und mit den optischen Konstanten kompletter G-Proteine verglichen. Durch Kreuzungen zwischen unspezifischen und spezifischen Polypeptidketten werden die Bedingungen einer spezifischen Rekombination geprüft. Sie sind insbesonders dann gegeben, wenn autologe, d.h. vom gleichen Myelomprotein stammende Polypeptidketten gemischt werden. Die Befunde werden in ihrer Beziehung zum Problem der Antikörperspezifität diskutiert.

---

Summary The results of measurements of the optical rotatory dispersion on H- and L-polypeptide chains of normal and myeloma proteins are reported Comparisons of the optical parameters with those of the whole G-proteins were performed. By mixing of normal or unspecific and myeloma or specific polypeptide chains the conditions of specific recombination were examined. Specific recombination occurs especially when autologous chains, that means polypeptide chains of an individual myeloma protein, are mixed. The implications of this finding are discussed with respect of the problem of antibody specifity.

---

---

Herrn Prof. Dr.H. E. Bock zum 65. Geburtstag.     

The role of interferon β in human cytomegalovirus-mediated inhibition of HLA DR induction on endothelial cells

Summary Human cytomegalovirus (HCMV), a member of the virus familyHerpesviridae that is associated with extensive worldwide morbidity and mortality in immunocompromised hosts, inhibits interferon- (IFN)-mediated induction of human leukocyte antigen (HLA) class II antigens on endothelial cells. In this study, the ability of HCMV-infected endothelial cells to synthesize interferon- (IFN), and the role of IFN in HCMV-mediated inhibition of HLA class II induction, was investigated. As detemined by an encephalomyocarditis virus protection assay, HCMV-infected endothelial cell culture supernatants contained 240 IU/ml of IFN type I activity, of which 99.9% was IFN, as compared to the absence of IFN in mock-infected culture supernatants. UV-irradiated supernatants from HCMV-infected cultures inhibited induction of HLA class II in noninfected cultures by 24%. This inhibition could be abolished with 500 NU/ml of anti-IFN antibody. Addition of anti-IFN antibody directly to HCMV-infected cultures mitigated but did not abolish HLA class II antigen inhibition. Dual immunohistochemistry for HCMV and HLA DR demonstrated that infected cells, in contrast to noninfected cells, were rarely induced to express HLA class II even in the presence of anti-IFN antibody. These findings suggest that HCMV inhibits induction of HLA class II antigens by IFN dependent and independent mechanisms.     

Modulation of Nav1.5 by β1- and β3-subunit co-expression in mammalian cells

Cardiac sodium channels (Na_v1.5) comprise a pore-forming -subunit and auxiliary -subunits that modulate channel function. In the heart, 1 is expressed throughout the atria and ventricles, whilst 3 is present only in the ventricles and Purkinje fibers. In view of this expression pattern, we determined the effects of 3 and 1 co-expression alone, and in combination, on Na_v1.5 stably expressed in Chinese hamster ovary cells. The current/voltage relationship was shifted –5 mV with either 1 or 3 co-expression alone and –10 mV with co-expression of both 1 and 3. In addition, 3 and 1/3 co-expression accelerated macroscopic current decay. There were significant hyperpolarizing shifts in equilibrium gating relationships with co-expression of 1 and 3 alone and in combination. Co-expression of 1/3 together resulted in a greater hyperpolarizing shift in channel availability, and an increase in the slopes of equilibrium gating relationships. Co-expression of 3 and 1/3, but not 1, slowed recovery from inactivation at –90 mV. Development of inactivation at –70 and –50 mV was accelerated by -subunit co-expression alone and in combination. -Subunit co-expression also reduced the late Na current measured at 200 ms. In conclusion, -subunits modulate Na_v1.5 gating with important differences between co-expression of 1 and 3 alone and 1/3 together.