BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1/KCNE1 (IKs)

Agsten, Marianne; Hessler, Sabine; Lehnert, Sandra; Volk, Tilmann; Rittger, Andrea; Hartmann, Stephanie; Raab, Christian; Kim, Doo Yeon; Groemer, Teja W.; Schwake, Michael; Alzheimer, Christian; Huth, Tobias

doi:10.1016/j.yjmcc.2015.10.006

Cited by 17 publications

(17 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the heart, IKs had an important role in cardiac action potential repolarization 37 . IKs contributed little to the ventricular action potential repolarization under normal circumstances 38 .…”

Section: Discussionmentioning

confidence: 99%

The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism

Zhao²,

Liang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Puerarin, a known isoflavone, is commonly found as a Chinese herb medicine. It is widely used in China to treat cardiac diseases such as angina, cardiac infarction and arrhythmia. However, its cardioprotective mechanism remains unclear. In this study, puerarin significantly prolonged ventricular action potential duration (APD) with a dosage dependent manner in the micromolar range on isolated rat ventricular myocytes. However, submicromolar puerarin had no effect on resting membrane potential (RMP), action potential amplitude (APA) and maximal velocity of depolarization (Vmax) of action potential. Only above the concentration of 10 mM, puerarin exhibited more aggressive effect on action potential, and shifted RMP to the positive direction. Millimolar concentrations of puerarin significantly inhibited inward rectified K+ channels in a dosage dependent manner, and exhibited bigger effects upon Kir2.1 vs Kir2.3 in transfected HEK293 cells. As low as micromolar range concentrations of puerarin significantly inhibited Kv7.1 and IKs. These inhibitory effects may due to the direct inhibition of puerarin upon channels not via the PKA-dependent pathway. These results provided direct preclinical evidence that puerarin prolonged APD via its inhibitory effect upon Kv7.1 and IKs, contributing to a better understanding the mechanism of puerarin cardioprotection in the treatment of cardiovascular diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism

Zhao²,

Liang

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…First answers to these questions come from a study, in which KCNQ1, KCNE1, and BACE1 (including its proteolytically inactive variant) were heterologously expressed in various combinations. 105 Major findings from this work are: First, BACE1 modulates currents mediated by KCNQ1 alone and by KCNQ1/KCNE1 complexes independent of its proteolytic function. Second, BACE1 slows activation and inactivation kinetics of KCNQ1/ KCNE1 currents, and third, the effects of BACE1 critically depend on cellular ATP levels: BACE1 reduced reconstituted I Ks in well-supplied cells, but counteracts current decline when ATP levels fall.…”

Section: Bace1 and Kcnq1/kcne1 (I Ks ) Currentsmentioning

confidence: 91%

“…105 Underscoring the significance of BACE1 for cardiac electrophysiology, atrial cardiomyocytes from BACE1 ¡/¡ mice show only about half the I Ks of wild type cells. 105 Since I Ks is thought to be mediated by KCNQ1/KCNE1 channel complexes, these findings strongly point to physiologically relevant BACE1/KCNQ interactions also in the heart. Compared to neurons, however, matters in the heart are complicated by the fact that KCNE1 (and KCNE2) were identified as substrates to sequential cleavage by BACE1 or a-secretase, and g-secretase.…”

Section: Bace1 and Kcnq1/kcne1 (I Ks ) Currentsmentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

Self Cite

View full text Add to dashboard Cite

b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

show abstract

“…While KCNQ1/KCNE1 channel complexes located in marginal cells of the stria vascularis serve to maintain the high K ϩ concentration of the endolymph, the prerequisite of the endochochlear potential, KCNQ4 provides the major K ϩ conductance of OHCs (Kharkovets et al, 2006). As we have reported previously BACE1 interacts with KCNQ channels including the subtypes present in the cochlea in a complex fashion, involving both enzymatic and nonenzymatic effects (Sachse et al, 2013;Agsten et al, 2015;Hessler et al, 2015;Lehnert et al, 2016). Thus, we wondered whether changes in KCNQ channel expression or function might contribute to the hearing deficit of BACE1 Ϫ/Ϫ mice.…”

Section: Bace1 Is Unlikely To Interact With K V 7 Channels In the Cocmentioning

confidence: 95%

“…Here, we investigated whether BACE1 is required for normal auditory function. Our study was prompted by the finding that Neuregulin-1, a functionally important substrate of BACE1, is expressed in the cochlea (Morley, 1998), and by our previous finding that BACE1 interacts with KCNQ1 and KCNQ4 (Agsten et al, 2015;Hessler et al, 2015), two voltage-dependent K ϩ channels which are essential for normal hearing (Jentsch, 2000;Maljevic et al, 2010). We found that BACE1 Ϫ/Ϫ mice exhibit significant hearing loss and attribute the phenotype to aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers.…”

Section: Introductionmentioning

confidence: 98%

β-Secretase BACE1 Is Required for Normal Cochlear Function

et al. 2019

Self Cite

View full text Add to dashboard Cite

Cleavage of amyloid precursor protein (APP) by ␤-secretase BACE1 initiates the production and accumulation of neurotoxic amyloid-␤ peptides, which is widely considered an essential pathogenic mechanism in Alzheimer's disease (AD). Here, we report that BACE1 is essential for normal auditory function. Compared with wild-type littermates, BACE1 Ϫ/Ϫ mice of either sex exhibit significant hearing deficits, as indicated by increased thresholds and reduced amplitudes in auditory brainstem responses (ABRs) and decreased distortion product otoacoustic emissions (DPOAEs). Immunohistochemistry revealed aberrant synaptic organization in the cochlea and hypomyelination of auditory nerve fibers as predominant neuropathological substrates of hearing loss in BACE1 Ϫ/Ϫ mice. In particular, we found that fibers of spiral ganglion neurons (SGN) close to the organ of Corti are disorganized and abnormally swollen. BACE1 deficiency also engenders organization defects in the postsynaptic compartment of SGN fibers with ectopic overexpression of PSD95 far outside the synaptic region. During postnatal development, auditory fiber myelination in BACE1 Ϫ/Ϫ mice lags behind dramatically and remains incomplete into adulthood. We relate the marked hypomyelination to the impaired processing of Neuregulin-1 when BACE1 is absent. To determine whether the cochlea of adult wild-type mice is susceptible to AD treatment-like suppression of BACE1, we administered the established BACE1 inhibitor NB-360 for 6 weeks. The drug suppressed BACE1 activity in the brain, but did not impair hearing performance and, upon neuropathological examination, did not produce the characteristic cochlear abnormalities of BACE1 Ϫ/Ϫ mice. Together, these data strongly suggest that the hearing loss of BACE1 knockout mice represents a developmental phenotype.

show abstract

BACE1 modulates gating of KCNQ1 (Kv7.1) and cardiac delayed rectifier KCNQ1/KCNE1 (IKs)

Cited by 17 publications

References 45 publications

The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism

The Effects of Puerarin on Rat Ventricular Myocytes and the Potential Mechanism

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

β-Secretase BACE1 Is Required for Normal Cochlear Function

Contact Info

Product

Resources

About