Gating movements and ion permeation in HCN4 pacemaker channels

Saponaro, Andrea; Bauer, Daniel; Giese, Maria; Swuec, Paolo; Porro, Alessandro; Gasparri, Federica; Sharifzadeh, Atiyeh Sadat; Chaves-Sanjuán, Antonio; Alberio, Laura; Parisi, Giacomo; Cerutti, Gabriele; Clarke, Oliver; Hamacher, Kay; Colecraft, Henry M.; Mancia, Filippo; Hendrickson, Wayne A.; Siegelbaum, Steven A.; DiFrancesco, Dario; Bolognesi, M.; Thiel, Gerhard; Santoro, Bina; Moroni, Anna

doi:10.1016/j.molcel.2021.05.033

Cited by 62 publications

(150 citation statements)

References 99 publications

(150 reference statements)

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“…The structures have indeed revealed unique intracellular regulatory modules, including both the HCN domain and Clinker/CNBD, which may allow for the targeting of HCN channels through allosteric modulation of pore gating properties. Furthermore, the recently determined structures of HCN4, the main cardiac isoform of HCN channels, have demonstrated critical differences in the relative arrangement of such regulatory modules (Saponaro et al, 2021), which may be exploited towards the development of isoform-specific drugs.…”

Section: Discussionmentioning

confidence: 99%

Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy

Merseburg

Kasemir

Buss

et al. 2021

Preprint

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De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo mutations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drugresistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Hcn1G380D/+ animals had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from HCN1 patients, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the need to tailor effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.

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Section: Discussionmentioning

confidence: 99%

Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy

Merseburg

Kasemir

Buss

et al. 2021

Preprint

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“…The SF structures include various constricted, stable conformations as well as asymmetric or even disordered states (see Figure 2 ). Recently, the TRPV1 and the HCN4 pore loop channels were discovered to have more subtle structural plasticity of the SF in their ability to adapt to different ion types ( Saponaro et al, 2021 ; Zhang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Commonly used structural biology techniques, such as X-ray crystallography or cryogenic electron microscopy (cryo-EM), lead to static snapshots of biological processes where the dynamics can easily be overlooked. Molecular dynamics (MD) simulations complement experimental approaches by obtaining information on the dynamics of previously determined structures ( Li et al, 2018 ; Kopec et al, 2019 ; Saponaro et al, 2021 ). However, MD simulations are still limited in terms of the timescale that can be sampled and sometimes suffer from the inaccuracy of force field parameters.…”

Section: Introductionmentioning

confidence: 99%

Structural Plasticity of the Selectivity Filter in Cation Channels

2021

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Ion channels allow for the passage of ions across biological membranes, which is essential for the functioning of a cell. In pore loop channels the selectivity filter (SF) is a conserved sequence that forms a constriction with multiple ion binding sites. It is becoming increasingly clear that there are several conformations and dynamic states of the SF in cation channels. Here we outline specific modes of structural plasticity observed in the SFs of various pore loop channels: disorder, asymmetry, and collapse. We summarize the multiple atomic structures with varying SF conformations as well as asymmetric and more dynamic states that were discovered recently using structural biology, spectroscopic, and computational methods. Overall, we discuss here that structural plasticity within the SF is a key molecular determinant of ion channel gating behavior.

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“…Las células del nodo sinusal presentan canales HCN (canales activados por hiperpolarizacióon y por nucleótidos cíclicos). Pertenecen a la superfamilia de canales de K + (Saponaro et al, 2021). Estos canales permiten generar potenciales de acción de manera controlada para mantener la frecuencia cardíaca y buen funcionamiento general del corazón (Giannetti et al, 2021;Guerra & Cinca, 2007).…”

Section: Introductionunclassified

“…Los canales funny se expresan altamente en regiones cardíacas espontáneamente activas. El canal tiene la base molecular de los canales activados por hiperpolarización y nucleótidos cíclicos (HCN) y comparten el mecanismo de activación (Saponaro et al, 2021;Scicchitano et al, 2012). Estos canales permiten el paso de Na + y K + .…”

Section: Introductionunclassified

Desarrollo de un simulador de la corriente funny del nodo sinusal para la enseñanza-aprendizaje

Pérez¹,

Lazalde²,

Chapero³

et al. 2021

S. F. J. of Dev.

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Las células del nodo sinusal generan la principal actividad eléctrica marcapaso del corazón. La actividad marcapaso se debe a la presencia de la corriente funny (If). Esta corriente iónica es entrante y se activa con la hiperpolarización en rangos de voltaje presentes durante la fase de despolarización diastólica; contrario a la mayoría de las corrientes iónicas que se activan con la despolarización. El canal funny es permeable a iones Na+ y K+. Generalmente, en el curso de biofísica a nivel de licenciatura los alumnos conocen algunos canales dependientes de voltaje del tipo de Hodgkin y Huxley que se activan con la despolarización. Sin embargo, no se estudia ningún canal que se active con una hiperpolarización. En este trabajo se diseñó y desarrolló un simulador para el estudio y comprensión de la corriente funny presente en el nodo sinusal del conejo. El simulador fue programado en lenguaje Visual Basic ver. 6.0 para ambiente Windows® de XP a Windows® 10. El usuario puede realizar los experimentos con la técnica de fijación de voltaje, modificar las variables y concentraciones de Na+ y K+ externos y observar el efecto en la amplitud de If y la cinética de la curva I-V. Se recomienda su uso como material didáctico de apoyo durante los cursos de biofísica y fisiología en una sala de cómputo o a distancia en cualquier computadora personal con recursos mínimos. The sinus node cells generate the main electric pacemaker activity of the heart. The pacemaker activity is due to the presence of the current funny (If). This ionic current is incoming and is activated with hypolarization in voltage ranges present during the diastolic depolarization phase, contrary to most ionic currents that are activated by depolarization. The funny channel is permeable to Na+ and K+ ions. Generally, students enrolled in the biophysics course at the undergraduate level are familiar with some voltage-gated channels of the Hodgkin and Huxley type. However, no channel that is activated by hiperpolarization is studied. In this work, a simulator was designed and developed for the study and understanding of the funny current present in the sinus node of rabbits. The simulator was programmed in Visual Basic Language ver. 6.0 for Windows® environment from XP to Windows® 10. The user can perform the experiments with the voltage clamp technique, modify the variables and concentrations of external Na+ and K+ and observe the effect on the amplitude of If and the kinetics of the curve I-V. It is recommended to be used as a support didactic material during biophysics and physiology courses in a computer room or remotely on any personal computer with minimal resources.

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Gating movements and ion permeation in HCN4 pacemaker channels

Cited by 62 publications

References 99 publications

Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy

Seizures, behavioral deficits and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy

Structural Plasticity of the Selectivity Filter in Cation Channels

Desarrollo de un simulador de la corriente funny del nodo sinusal para la enseñanza-aprendizaje

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