KCNQ1 loss-of-function mutation impairs gastric acid secretion in mice.

The KCNQ1 channel is abundantly expressed in the gastric parietal cells. Although the functional coupling of KCNQ1 with the H(+)/K(+)-ATPase has already been confirmed on the basis of pharmacological kinetics, the effect of a KCNQ1 loss-of-function mutation on gastric acidification remains unclear. In this study, parietal cells and gastric glands from both C57BL/6 J mice (normal control) and J343 mice (mice with a KCNQ1 loss-of-function mutation) were isolated to study the effects of KCNQ1 on gastric acidification. We found that the mutation limited intracellular acidification of parietal cells and H(+) secretion of the stomach in response to histamine. Thus, a KCNQ1 loss-of-function mutation may impair gastric acid secretion.

Kir2.3 knock-down decreases IK1 current in neonatal rat cardiomyocytes.

Inward rectifier potassium Kir2.x channels mediate cardiac inward rectifier potassium currents (I(K1)). As a subunit of Kir2.x, the physiological role of Kir2.3 in native cardiomyocytes has not been reported. This study shows that Kir2.3 knock-down remarkably down-regulates Kir2.3 expression (Kir2.3 protein was reduced to 19.91+/-3.24% on the 2nd or 3rd day) and I(K1) current densities (at -120 mV, control vs. knock-down: -5.03+/-0.24 pA/pF, n=5 vs. -1.16+/-0.19 pA/pF, n=7, P<0.001) in neonatal rat cardiomyocytes. The data suggest that Kir2.3 plays a potentially important role in I(K1) currents in neonatal rat cardiomyocytes.

Human KCNQ1 S140G mutation is associated with atrioventricular blocks.

BACKGROUND: We recently reported that an S140G mutation in human KCNQ1, an alpha subunit of potassium channels, was involved in the pathogenesis of familial atrial fibrillation (AF), but it is not clear whether the mutation is associated with other cardiac arrhythmias. OBJECTIVE: The purpose of this study was to further explore the association of the KCNQ1 S140G mutation with cardiac arrhythmias. METHODS: We produced a transgenic mouse model with myocardium-specific expression of the human KCNQ1 S140G mutation under the control of an alpha-cardiac myosin heavy chain promoter by standard transgenic procedure and evaluated the relationship between the KCNQ1 mutation and its phenotypes in a human family. RESULTS: Four lines of transgenic mice were established with a high level of human KCNQ1 S140G expression in the heart. Frequent episodes of first-, second-, advanced-, or third-degree atrioventricular block (AVB) occurred in at least 65% of transgenic descendants from the four lines. However, none of the five wild-type transgenic lines presented with AVBs. HMR1556, a KCNQ1-specific blocker, can terminate the AVBs. With the exception of at most three AF individuals, at least 13 AF patients were found to show obviously slow ventricular response, which may be one manifestation of AVBs. Interestingly, AF was not detected in these transgenic mice. CONCLUSION: The results suggest that human KCNQ1 S140G is also likely to be a causative mutation responsible for AVBs. The transgenic mouse model is a potential tool to explore mechanisms of AVBs.

Spatial heterogeneity of muscarinic type 2 receptors in the atrium.

Atrial fibrillation (AF) is the most common arrhythmia in clinical practices. Mediated by muscarinic type 2 receptors (M(2)Rs), acetylcholine affects electrophysiological activities of atrial myocytes and may contribute to the onset of AF. In order to characterize the distribution of M(2)Rs in the atrial myocardium, different atrial regions in both the SD rat and human were dissected. Atrial myocytes were isolated with type II collagenase. The M(2)Rs expression in these atrial tissues and myocytes was detected by immunofluorescent staining and confocal laser scanning biological microscope. The results showed the highest density of M(2)Rs in atrial myocytes of the left atrial posterior wall. It is concluded that there is a marked spatial heterogeneity in the expression of the M(2)Rs in the atrium, which might create a substrate that would favor the initiation and maintenance of acetylcholine-induced AF.

Stretch-induced alterations of human Kir2.1 channel currents.

The inward rectifier potassium channel, Kir2.1, contributes to the I(K1) current in cardiac myocytes and is closely associated with atrial fibrillation. Strong evidences have shown that atrial dilatation or stretch may result in atrial fibrillation. However, the role of Kir2.1 channels in the stretch-mediated atrial fibrillation is not clear. In this study, we constructed the recombinant plasmid of KCNJ2 that encodes the Kir2.1 channel and expressed it in CHO-K1 cells. We recorded I(K1) currents using the whole-cell patch clamping technique. Our data showed that I(K1) currents were significantly larger under stretch in the hypotonic solution than under non-stretch in the iso-osmotic solution, and the activation kinetics of the Kir2.1 channel were changed markedly by stretch as well. Thus, atrial stretch in human heart might result in excessive I(K1) currents, which is likely to increase the resting membrane potential and decrease the effective refractory period, to initiate and/or maintain atrial fibrillation.

A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation.

The inward rectifier K(+) channel Kir2.1 mediates the potassium I(K1) current in the heart. It is encoded by KCNJ2 gene that has been linked to Andersen's syndrome. Recently, strong evidences showed that Kir2.1 channels were associated with mouse atrial fibrillation (AF), therefore we hypothesized that KCNJ2 was associated with familial AF. Thirty Chinese AF kindreds were evaluated for mutations in KCNJ2 gene. A valine-to-isoleucine mutation at position 93 (V93I) of Kir2.1 was found in all affected members in one kindred. This valine and its flanking sequence is highly conserved in Kir2.1 proteins among different species. Functional analysis of the V93I mutant demonstrated a gain-of-function consequence on the Kir2.1 current. This effect is opposed to the loss-of-function effect of previously reported mutations in Andersen's syndrome. Kir2.1 V93I mutation may play a role in initiating and/or maintaining AF by increasing the activity of the inward rectifier K(+) channel.

Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. We first reported an S140G mutation of KCNQ1, an alpha subunit of potassium channels, in one Chinese kindred with AF. However, the molecular defects and cellular mechanisms in most patients with AF remain to be identified. We evaluated 28 unrelated Chinese kindreds with AF and sequenced eight genes of potassium channels (KCNQ1, HERG, KCNE1, KCNE2, KCNE3, KCNE4, KCNE5, and KCNJ2). An arginine-to-cysteine mutation at position 27 (R27C) of KCNE2, the beta subunit of the KCNQ1-KCNE2 channel responsible for a background potassium current, was found in 2 of the 28 probands. The mutation was present in all affected members in the two kindreds and was absent in 462 healthy unrelated Chinese subjects. Similar to KCNQ1 S140G, the mutation had a gain-of-function effect on the KCNQ1-KCNE2 channel; unlike long QT syndrome-associated KCNE2 mutations, it did not alter HERG-KCNE2 current. The mutation did not alter the functions of the HCN channel family either. Thus, KCNE2 R27C is a gain-of-function mutation associated with the initiation and/or maintenance of AF.