Elisa Tavazzani

University of Pavia

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Giancarlo Russo

University of Pavia

Sergio Masetto

University of Pavia

Ivo Prigioni

University of Pavia

Paolo Spaiardi

University of Pavia

Marco Manca

Johns Hopkins Medicine

Silvia G. Priori

Istituti Clinici Scientifici Maugeri

Giovanni Lentini

University of Bari Aldo Moro

Donatella Contini

University of Illinois Chicago

Carlo Camilloni

University of Milan

Alessandro Trancuccio

Istituti Clinici Scientifici Maugeri

Cooperative Institutions

University of Pavia

Istituti Clinici Scientifici Maugeri

Spanish National Centre for Cardiovascular Research

University of Milan

University of Bari Aldo Moro

Fondazione Salvatore Maugeri

Centro de Investigación en Red en Enfermedades Cardiovasculares

Centro de Investigación Biomédica en Red

Istituti di Ricovero e Cura a Carattere Scientifico

University of Padua

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CCDC 2209758: Experimental Crystal Structure Determination

The Cambridge Structural Database (2023)

Gualtiero Milani Roberta Budriesi Elisa Tavazzani Maria Maddalena Cavalluzzi Laura Mattioli

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccdc.csd.cc2d5fjk

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Citations (0)

Distinct roles of Eps8 in the maturation of cochlear and vestibular hair cells

Neuroscience (2016)

Elisa Tavazzani Paolo Spaiardi Valeria Zampini Donatella Contini Marco Manca

Stereocilia (inner ear)

Kinocilium

10.1016/j.neuroscience.2016.04.038

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Citations (7)

Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome

Nature Cardiovascular Research (2023)

Andreu Porta‐Sánchez Andrea Mazzanti Carmen Tarifa Deni Kukavica Alessandro Trancuccio

Abstract Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C , known to impair Ca V 1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca 2+ overload and decreased peak I Na current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

Reentry

10.1038/s44161-023-00393-w

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Citations (7)

Allosteric gating of K,L channels expressed in mouse vestibular Type I hair cells

Paolo Spaiardi Elisa Tavazzani Marco Manca Ivo Prigioni Giancarlo Russo

Utricle

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Molecular Insights into the Rescue Mechanism of an hERG Activator Against Severe LQT2 Mutations

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Amit Kumawat Elisa Tavazzani Giovanni Lentini Alessandro Trancuccio Deni Kukavica

Mutations in the hERG potassium channel are a major cause of long QT syndrome type 2 (LQT2), which can lead to sudden cardiac death. The hERG channel plays a critical role in the repolarization of the myocardial action potential, and loss-of-function mutations prolong cardiac repolarization. In this study, we investigated the efficacy and mechanism of ICA-105574, an hERG activator, in shortening the duration of cardiac repolarization in severe LQT2 variants. We characterized the in vivo efficacy of ICA-105574 in shortening the QT duration in an animal model and in vitro in enhancing IKr current in cellular models mimicking severe hERG channel mutations (A561V, G628S, and L779P). We then used molecular dynamics simulations to investigate the molecular mechanism of ICA-105574 action. In vivo, ICA-105574 significantly shortened the QT interval. LQT2 mutations drastically reduced IKr amplitude and suppressed tail currents in cellular models. ICA-105574 restored IKr in A561V and G628S. Finally, in silico data showed that ICA-105574 stabilizes a pattern of interactions similar to gain-of-function SQT1 mutations and can reverse the G628S modifications, through an allosteric network linking the binding site to the selectivity filter and the S5P turret helix, thereby restoring its K+ ion permeability. Our results support the development of hERG activators as pharmacological molecules against some severe LQT2 mutations and suggest that molecular dynamics simulations can be used to test the ability of molecules to modulate hERG function in silico, paving the way for the rational design of new hERG activators.

hERG

10.1101/2024.03.13.584147

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Citations (2)

An allosteric gating model recapitulates the biophysical properties of I_K,L expressed in mouse vestibular type I hair cells

The Journal of Physiology (2017)

Paolo Spaiardi Elisa Tavazzani Marco Manca Verónica Milesi Giancarlo Russo

Vestibular type I and type II hair cells and their afferent fibres send information to the brain regarding the position and movement of the head. The characteristic feature of type I hair cells is the expression of a low-voltage-activated outward rectifying K+ current, IK,L , whose biophysical properties and molecular identity are still largely unknown. In vitro, the afferent nerve calyx surrounding type I hair cells causes unstable intercellular K+ concentrations, altering the biophysical properties of IK,L . We found that in the absence of the calyx, IK,L in type I hair cells exhibited unique biophysical activation properties, which were faithfully reproduced by an allosteric channel gating scheme. These results form the basis for a molecular and pharmacological identification of IK,L .Type I and type II hair cells are the sensory receptors of the mammalian vestibular epithelia. Type I hair cells are characterized by their basolateral membrane being enveloped in a single large afferent nerve terminal, named the calyx, and by the expression of a low-voltage-activated outward rectifying K+ current, IK,L . The biophysical properties and molecular profile of IK,L are still largely unknown. By using the patch-clamp whole-cell technique, we examined the voltage- and time-dependent properties of IK,L in type I hair cells of the mouse semicircular canal. We found that the biophysical properties of IK,L were affected by an unstable K+ equilibrium potential (Veq K+ ). Both the outward and inward K+ currents shifted Veq K+ consistent with K+ accumulation or depletion, respectively, in the extracellular space, which we attributed to a residual calyx attached to the basolateral membrane of the hair cells. We therefore optimized the hair cell dissociation protocol in order to isolate mature type I hair cells without their calyx. In these cells, the uncontaminated IK,L showed a half-activation at -79.6 mV and a steep voltage dependence (2.8 mV). IK,L also showed complex activation and deactivation kinetics, which we faithfully reproduced by an allosteric channel gating scheme where the channel is able to open from all (five) closed states. The 'early' open states substantially contribute to IK,L activation at negative voltages. This study provides the first complete description of the 'native' biophysical properties of IK,L in adult mouse vestibular type I hair cells.

Reversal potential

Vestibular nerve

10.1113/jp274202

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Citations (16)

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1

Journal of the American College of Cardiology (2020)

Andrea Mazzanti Dmitri Guz Alessandro Trancuccio Eleonora Pagan Deni Kukavica

Risk Stratification

Stratification (seeds)

10.1016/j.jacc.2020.02.033

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Citations (58)

K+ Accumulation and Clearance in the Calyx Synaptic Cleft of Type I Mouse Vestibular Hair Cells

Neuroscience (2019)

Paolo Spaiardi Elisa Tavazzani Marco Manca Giancarlo Russo Ivo Prigioni

Vestibular organs of Amniotes contain two types of sensory cells, named Type I and Type II hair cells. While Type II hair cells are contacted by several small bouton nerve terminals, Type I hair cells receive a giant terminal, called a calyx, which encloses their basolateral membrane almost completely. Both hair cell types release glutamate, which depolarizes the afferent terminal by binding to AMPA post-synaptic receptors. However, there is evidence that non-vesicular signal transmission also occurs at the Type I hair cell-calyx synapse, possibly involving direct depolarization of the calyx by K+ exiting the hair cell. To better investigate this aspect, we performed whole-cell patch-clamp recordings from mouse Type I hair cells or their associated calyx. We found that [K+] in the calyceal synaptic cleft is elevated at rest relative to the interstitial (extracellular) solution and can increase or decrease during hair cell depolarization or repolarization, respectively. The change in [K+] was primarily driven by GK,L, the low-voltage-activated, non-inactivating K+ conductance specifically expressed by Type I hair cells. Simple diffusion of K+ between the cleft and the extracellular compartment appeared substantially restricted by the calyx inner membrane, with the ion channels and active transporters playing a crucial role in regulating intercellular [K+]. Calyx recordings were consistent with K+ leaving the synaptic cleft through postsynaptic voltage-gated K+ channels involving KV1 and KV7 subunits. The above scenario is consistent with direct depolarization and hyperpolarization of the calyx membrane potential by intercellular K+.

Calyx

Synaptic cleft

10.1016/j.neuroscience.2019.11.028

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Citations (23)

Precision medicine: a new era for inner ear diseases

Frontiers in Pharmacology (2024)

Elisa Tavazzani Paolo Spaiardi Donatella Contini Giulio Sancini Giancarlo Russo

The inner ear is the organ responsible for hearing and balance. Inner ear dysfunction can be the result of infection, trauma, ototoxic drugs, genetic mutation or predisposition. Often, like for Ménière disease, the cause is unknown. Due to the complex access to the inner ear as a fluid-filled cavity within the temporal bone of the skull, effective diagnosis of inner ear pathologies and targeted drug delivery pose significant challenges. Samples of inner ear fluids can only be collected during surgery because the available procedures damage the tiny and fragile structures of the inner ear. Concerning drug administration, the final dose, kinetics, and targets cannot be controlled. Overcoming these limitations is crucial for successful inner ear precision medicine. Recently, notable advancements in microneedle technologies offer the potential for safe sampling of inner ear fluids and local treatment. Ultrasharp microneedles can reach the inner ear fluids with minimal damage to the organ, collect μl amounts of perilymph, and deliver therapeutic agents in loco . This review highlights the potential of ultrasharp microneedles, combined with nano vectors and gene therapy, to effectively treat inner ear diseases of different etiology on an individual basis. Though further research is necessary to translate these innovative approaches into clinical practice, these technologies may represent a true breakthrough in the clinical approach to inner ear diseases, ushering in a new era of personalized medicine.

Perilymph

Outer ear

Personalized Medicine

10.3389/fphar.2024.1328460

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Citations (3)

Glutamic acid decarboxylase 67 expression by a distinct population of mouse vestibular supporting cells

Frontiers in Cellular Neuroscience (2014)

Elisa Tavazzani Simona Tritto Paolo Spaiardi Laura Botta Marco Manca

The function of the enzyme glutamate decarboxylase (GAD) is to convert glutamate in γ-aminobutyric acid (GABA). Glutamate decarboxylase exists as two major isoforms, termed GAD65 and GAD67, that are usually expressed in GABA-containing neurons in the central nervous system. GAD65 has been proposed to be associated with GABA exocytosis whereas GAD67 with GABA metabolism. In the present immunofluorescence study, we have investigated the presence of the two GAD isoforms in the semicircular canal cristae of wild type and GAD67-GFP knock-in mice. While no evidence for GAD65 expression was found, GAD67 was detected in a distinct population of peripherally-located supporting cells, but not in hair cells or in centrally-located supporting cells. GABA, on the other hand, was found in all supporting cells. The present result indicate that only a discrete population of supporting cells use GAD67 to synthesize GABA. This is the first report of a marker that allows to distinguish two populations of supporting cells in the vestibular epithelium. On the other hand, the lack of GABA and GAD enzymes in hair cells excludes its involvement in afferent transmission.

10.3389/fncel.2014.00428

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Citations (16)