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The effects of the hKvbeta1.2 beta subunit of the human atrium on hKv1.5 currents were analyzed in an experimental model in which the Kvbeta subunit functioned as a channel-blocking particle. The currents from the hKv1.5 delayed rectifier K+ channel in Xenopus oocytes were rapidly activated to a plateau current level during pulses to a range of potentials in the positive voltage range. Furthermore, hKvbeta1.2 confered rapid inactivation on the delayed rectifier K+ channel hKv1.5.

The effects of the amphiphilic substance niflumic acid (NFA) were examined in myocytes isolated from the sino-atrial node of the rabbit heart. NFA (50 and 500 μM), for 30-60 s, produced a reversible negative chronotropic effect by reducing the rate of diastolic depolarization, suggesting an inhibitory effect on the hyperpolarization-activated 'pacemaker' current ( i). NFA (from 0.05 to 500 μM) inhibited i by modifying the current kinetics, without alteration of the conductance. This was shown by evidence indicating that: (1) NFA inhibited i during hyperpolarizing pulses to the mid-point of i activation but not at fully activating voltages; (2) the slope and reversal potential of the fully activated current/voltage (I/V) relation were not altered by NFA, indicating no change in slope conductance or ion selectivity; and (3) hyperpolarizing ramp protocols confirmed the lack of action of 50 μM NFA on the fully activated current and a shift of approximately −8 mV Although similar to inhibition by acetylcholine (ACh), inhibition by NFA was only partly additive with the action of ACh and was not altered by atropine or pertussis toxin, both of which eliminated the action of ACh. The effect of NFA was present after stimulation of adenylate cyclase by forskolin and after inhibition of phosphodiesterase by isobutylmethylxanthine (IBMX). In cell-attached patch measurements, NFA applied externally did not affect i measured in the patch. Finally, application of NFA to the cytoplasmic side of excised patches did not alter the current in the absence or presence of adenosine 3′,5′-cyclic monophosphate (cAMP). These results suggest an external, membrane-delimited action of NFA on i. [ABSTRACT FROM AUTHOR]

Ever since they were first observed in Purkinje fibers of the heart, funny channels have had close connections to potassium channels. Indeed, funny channels were initially thought to produce a potassium current in the heart called I K2 . However, funny channels are completely unlike potassium channels in ways that make their contributions to the physiology of cells unique. An important difference is the greater ability for sodium to permeate funny channels. Although it does not flow through the funny channel as easily as does potassium, sodium does permeate well enough to allow for depolarization of cells following a strong hyperpolarization. This is critical for the function of funny channels in places like the heart and brain. Computational analyses using recent structures of the funny channels have provided a possible mechanism for their unusual permeation properties., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Physiological Society.)

Competing Interests: Declaration of competing interest None.

Episodic Ataxia Type 1 is an autosomal dominant disorder characterized by episodes of ataxia and myokymia. It is associated with mutations in the KCNA1 voltage-gated potassium channel gene. In the present study, we describe a family with novel clinical features including persistent cerebellar dysfunction, cerebellar atrophy, and cognitive delay. All affected family members have myokymia and epilepsy, but only one individual has episodes of vertigo. Additional features include postural abnormalities, episodic stiffness and weakness. A novel KCNA1 mutation (c.1222G>T) which replaces a highly conserved valine with leucine at position 408 (p.Val408Leu) was identified in affected family members, and was found to augment the ability of the channel to inactivate. Together, our data suggests that KCNA1 mutations are associated with a broader clinical phenotype, which may include persistent cerebellar dysfunction and cognitive delay.

Purpose: Hereditary long QT syndrome is named for a prolonged QT interval reflecting predisposition to ventricular arrhythmias and sudden death. A high rate in a remote, northern Canadian First Nations community was brought to attention., Methods: Two severely affected index cases and 122 relatives were ascertained using community-based participatory research principles. Genetic sequencing of five known genes responsible for long QT syndrome was carried out on the index cases, leading to the identification of a novel missense mutation. Functional properties of the identified mutation were studied in transfected mouse ltk- cells using whole cell patch clamp techniques. Corrected QT interval measurements were obtained from participants and subsequent genotyping of relatives was carried out., Results: In the two index cases, a novel missense mutation (V205M) was identified in the S3 transmembrane helix of KvLQT1, the pore forming domain of the IKs channel complex. In transfected mouse ltk-cells the V205M mutation suppressed IKs by causing a dramatic depolarizing shift in activation voltage coupled with acceleration of channel deactivation. Twenty-two mutation carriers had a significantly higher mean corrected QT interval than noncarriers (465 +/- 28 milliseconds vs. 434 +/- 26 milliseconds, P < 0.0001); however, 30% of carriers had a corrected QT interval below 440 milliseconds., Conclusion: A novel KCNQ1 mutation in this founder population likely confers increased susceptibility to arrhythmias because of decreased IKs current. Even with a common mutation within a relatively homogenous population, clinical expression remains variable, exemplifying the multifactorial nature of long QT syndrome, and supporting the difficulty of definitive diagnosis without genetic testing. A community participatory approach enabled a comprehensive evaluation of the impact.

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP-sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.

Experiments were carried out to determine whether coinjection of Kvalpha1.2 with inactivating and noninactivating Kvbeta subunits would produce currents with intermediate kinetics and channel complexes containing a mixture of these subunits. Upon coexpression with a saturating amount of Kvbeta1.2 and increasing levels of a noninactivating deletion mutant of Kvbeta1.2, we show that macroscopic Kvalpha1.2 currents have levels of fractional inactivation and inactivation time constants that are intermediate between those obtained with either the inactivating Kvbeta1.2 or the noninactivating Kvbeta1.2 mutant. We also find that coexpression of Kvalpha1.2 with saturating amounts of Kvbeta1.2 and the deletion mutant produces a population of single channels with properties intermediate to either the inactivating or noninactivating parental phenotype. Our data can best be explained by the presence of an intermediate population of heterooligomeric channels consisting of Kvalpha1.2 with different combinations of both types of subunits. Since Kvalpha1.2 subunits coexist in cells with inactivating and noninactivating Kvbeta subunits, our findings suggest that heterooligomeric assembly of these subunits occurs to increase the range of K+ current kinetics and expression levels.

The enteric nervous system consists of two major plexi, the submucous (Meissner's) lying between the circular muscle and mucosal layers, and the myenteric (Auerbach's) between the circular and longitudinal muscle. In recent years, it has become apparent that the chemical coding of the neurons in these two plexi differs significantly within a single species (1) and between species (2). The functional significance of the chemical coding of the enteric neurons is difficult to assess in vivo because of the absence of knowledge about the electrophysiological properties of the neurons and the regulation of neuropeptide/neurotransmitter release.

The objectives of these experiments were to localize vasoactive intestinal peptide immunoreactivity (VIP-IR) in the intracardiac ganglia of the interatrial septum of the rabbit heart and to examine the effects of vasoactive intestinal peptide (VIP) on the isolated perfused rabbit heart. Cell bodies of neurones containing VIP-IR were located in the interatrial septa of rabbit hearts by using immunocytochemistry. In addition, the effects of substance P (SP), neurokinin A (NKA), and neurokinin B (NKB) on the isolated rabbit heart were compared with those of VIP. Bolus injections of SP, NKA, VIP, and NKB caused dose-dependent decreases in the perfusion pressure of hearts perfused at constant flow with ED50 values of 2.73 +/- 0.10 fmol (n = 6), 0.18 +/- 0.01 pmol (n = 8), 93.75 +/- 1.88 pmol (n = 6), and 75.00 +/- 3.06 pmol (n = 6), respectively. The slope of the dose-response curve of VIP was much greater than those of SP and NKA, suggesting the presence of one receptor subtype for VIP and multiple receptor subtypes for the neurokinins on rabbit coronary vessels. Differences in the slopes of the dose-response curves and potency may reflect differences in the mechanism of vasodilatation. The maximal values of vasodilatation of all of the peptides did not differ. None of the peptides produced significant changes in heart rate, left ventricular pressure, or contractility. These results suggest that VIP found in the intracardiac neurones of the rabbit heart can mediate coronary vasodilatation.

A cervical (C2) spinal section was carried out in anaesthetized, neuromuscularly blocked cats and the vascularly isolated hindlimbs were independently perfused at constant flow with blood taken from the abdominal aorta. One leg was denervated by sectioning the lumbar sympathetic chain. The animals were hyperventilated in 100% O2 and 5% or 10% CO2 in O2 was administered without altering the rate or tidal volume of the respirator. Increasing paCO2 (mm Hg) from 16.36 +/- 0.84 to 37.48 +/- 1.03 and to 62.23 +/- 2.23, induced a significant early vasoconstriction (P1) followed by a later more prolonged vasoconstriction (P2) in the innervated leg, while only a significant P2 response was present in the sympathetically denervated leg. A significant increase in systemic arterial pressure (SAP) was also observed with no change in heart rate (HR). After bilateral adrenalectomy increasing paCO2 from 17.16 +/- 0.66 to 37.96 +/- 1.21 and to 64.20 +/- 1.55, induced smaller but significant P1 and P2 responses in the innervated leg but only a significant P2 response was induced in the denervated leg. These results suggest that the early vasoconstriction was mainly due to activation of lumbar sympathetic neurons, while the late vasoconstriction was caused by the release of adrenal catecholamines and possibly other unidentified vasoconstrictor substances.