Electromechanical coupling mechanism for activation and inactivation of an HCN channel

Dai, Gucan; Aman, Teresa K.; DiMaio, Frank; Zagotta, William N.

doi:10.1038/s41467-021-23062-7

Cited by 21 publications

(28 citation statements)

References 57 publications

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“…It has been shown that the intracellular cyclic nucleotide–binding domain (CNBD) [ 78 ] exerts an inhibiting effect on the transmembrane core of the channel. Binding of cyclic nucleotides to the CNBD leads to a conformational change that is propagated through the C-linker and ultimately relieves inhibition of the transmembrane region, thereby facilitating channel opening [ 14 , 60 , 64 , 74 ]. In this way, changes in the intracellular cAMP concentration significantly regulate HCN channel activity within the physiological range of membrane potentials [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Paradigm shift: new concepts for HCN4 function in cardiac pacemaking

Hennis

Biel

Fenske

et al. 2022

Pflugers Arch - Eur J Physiol

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Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are the molecular correlate of the If current and are critically involved in controlling neuronal excitability and the autonomous rhythm of the heart. The HCN4 isoform is the main HCN channel subtype expressed in the sinoatrial node (SAN), a tissue composed of specialized pacemaker cells responsible for generating the intrinsic heartbeat. More than 40 years ago, the If current was first discovered in rabbit SAN tissue. Along with this discovery, a theory was proposed that cyclic adenosine monophosphate–dependent modulation of If mediates heart rate regulation by the autonomic nervous system—a process called chronotropic effect. However, up to the present day, this classical theory could not be reliably validated. Recently, new concepts emerged confirming that HCN4 channels indeed play an important role in heart rate regulation. However, the cellular mechanism by which HCN4 controls heart rate turned out to be completely different than originally postulated. Here, we review the latest findings regarding the physiological role of HCN4 in the SAN. We describe a newly discovered mechanism underlying heart rate regulation by HCN4 at the tissue and single cell levels, and we discuss these observations in the context of results from previously studied HCN4 mouse models.

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Section: Introductionmentioning

confidence: 99%

Paradigm shift: new concepts for HCN4 function in cardiac pacemaking

Hennis

Biel

Fenske

et al. 2022

Pflugers Arch - Eur J Physiol

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“…When the translation machinery arrives at the TAG stop-codon site, translation continues by including L-Anap and avoiding mRNA chain termination. This strategy has been previously shown to achieve satisfactory incorporation of L-Anap into exogenously expressed recombinant membrane proteins ( Dai et al, 2019 ; Dai et al, 2021 ; Dai and Zagotta, 2017 ). In our experiments, cells grown without applying pANAP plasmid (tRNA/aaRS), but with BACE1-L500TAG cDNA transfected and L-Anap in media were used as negative controls for the FRET experiments.…”

Section: Resultsmentioning

confidence: 99%

Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1

Dai

2022

Journal of General Physiology

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β-Secretase 1 (β-site amyloid precursor protein [APP]-cleaving enzyme 1, BACE1) plays a crucial role in the amyloidogenesis of Alzheimer’s disease (AD). BACE1 was also discovered to act like an auxiliary subunit to modulate neuronal KCNQ2/3 channels independently of its proteolytic function. BACE1 is palmitoylated at its carboxyl-terminal region, which brings BACE1 to ordered, cholesterol-rich membrane microdomains (lipid rafts). However, the physiological consequences of this specific localization of BACE1 remain elusive. Using spectral Förster resonance energy transfer (FRET), BACE1 and KCNQ2/3 channels were confirmed to form a signaling complex, a phenomenon that was relatively independent of the palmitoylation of BACE1. Nevertheless, palmitoylation of BACE1 was required for recruitment of KCNQ2/3 channels to lipid-raft domains. Two fluorescent probes, designated L10 and S15, were used to label lipid-raft and non-raft domains of the plasma membrane, respectively. Coexpressing BACE1 substantially elevated FRET between L10 and KCNQ2/3, whereas the BACE1-4C/A quadruple mutation failed to produce this effect. In contrast, BACE1 had no significant effect on FRET between S15 probes and KCNQ2/3 channels. A reduction of BACE1-dependent FRET between raft-targeting L10 probes and KCNQ2/3 channels by applying the cholesterol-extracting reagent methyl-β-cyclodextrin (MβCD), raft-disrupting general anesthetics, or pharmacological inhibitors of palmitoylation, all supported the hypothesis of the palmitoylation-dependent and raft-specific localization of KCNQ2/3 channels. Furthermore, mutating the four carboxyl-terminal cysteines (4C/A) of BACE1 abolished the BACE1-dependent increase of FRET between KCNQ2/3 and the lipid raft–specific protein caveolin 1. Taking these data collectively, we propose that the AD-related protein BACE1 underlies the localization of a neuronal potassium channel.

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“…Using transition metal ion FRET In spHCN channels, Dai and coworkers determined by combining PCF and molecular modeling differences in the structural rearrangements between activated and inactivated channels and discovered that removing cAMP produced a largely rigid-body rotation of the C-linker relative to the transmembrane domain [ 98 ].…”

Section: Methods To Analyze Activation Gating Preceding Pore Openingmentioning

confidence: 99%

Enlightening activation gating in P2X receptors

Sattler

Benndorf

2022

Purinergic Signalling

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P2X receptors are trimeric nonselective cation channels gated by ATP. They assemble from seven distinct subunit isoforms as either homo- or heteromeric complexes and contain three extracellularly located binding sites for ATP. P2X receptors are expressed in nearly all tissues and are there involved in physiological processes like synaptic transmission, pain, and inflammation. Thus, they are a challenging pharmacological target. The determination of crystal and cryo-EM structures of several isoforms in the last decade in closed, open, and desensitized states has provided a firm basis for interpreting the huge amount of functional and biochemical data. Electrophysiological characterization in conjugation with optical approaches has generated significant insights into structure–function relationships of P2X receptors. This review focuses on novel optical and related approaches to better understand the conformational changes underlying the activation of these receptors.

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Electromechanical coupling mechanism for activation and inactivation of an HCN channel

Cited by 21 publications

References 57 publications

Paradigm shift: new concepts for HCN4 function in cardiac pacemaking

Paradigm shift: new concepts for HCN4 function in cardiac pacemaking

Neuronal KCNQ2/3 channels are recruited to lipid raft microdomains by palmitoylation of BACE1

Enlightening activation gating in P2X receptors

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