Phung N. Thai

University of California, Davis

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Nipavan Chiamvimonvat

University of California, Davis

Padmini Sirish

University of California, Davis

Pauline Trinh

University of California, Davis

Ebenezer N. Yamoah

University of Nevada, Reno

Eamonn J. Dickson

University of California, Davis

Rose E. Dixon

University of California, Davis

Lu Ren

Central South University

Xiao-Dong Zhang

Montefiore Medical Center

Elena N. Dedkova

University of California, Davis

Heather C. Spooner

University of California, Davis

Cooperative Institutions

University of California, Davis

University of Nevada, Reno

VA Northern California Health Care System

University of California, San Diego

Laboratoire de Biologie Physico-Chimique des Protéines Membranaires

VA San Diego Healthcare System

University of California Davis Medical Center

UC Davis Health System

University of California System

University of Washington

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Atomistic mechanisms of the regulation of small-conductance Ca ²⁺ -activated K ⁺ channel (SK2) by PIP2

Proceedings of the National Academy of Sciences (2024)

Ryan L. Woltz Yang Zheng Woori Choi Khoa Ngo Pauline Trinh

Small-conductance Ca 2+ -activated K + channels (SK, K Ca 2) are gated solely by intracellular microdomain Ca 2+ . The channel has emerged as a therapeutic target for cardiac arrhythmias. Calmodulin (CaM) interacts with the CaM binding domain (CaMBD) of the SK channels, serving as the obligatory Ca 2+ sensor to gate the channels. In heterologous expression systems, phosphatidylinositol 4,5-bisphosphate (PIP2) coordinates with CaM in regulating SK channels. However, the roles and mechanisms of PIP2 in regulating SK channels in cardiomyocytes remain unknown. Here, optogenetics, magnetic nanoparticles, combined with Rosetta structural modeling, and molecular dynamics (MD) simulations revealed the atomistic mechanisms of how PIP2 works in concert with Ca 2+ -CaM in the SK channel activation. Our computational study affords evidence for the critical role of the amino acid residue R395 in the S6 transmembrane segment, which is localized in propinquity to the intracellular hydrophobic gate. This residue forms a salt bridge with residue E398 in the S6 transmembrane segment from the adjacent subunit. Both R395 and E398 are conserved in all known isoforms of SK channels. Our findings suggest that the binding of PIP2 to R395 residue disrupts the R395:E398 salt bridge, increasing the flexibility of the transmembrane segment S6 and the activation of the channel. Importantly, our findings serve as a platform for testing of structural-based drug designs for therapeutic inhibitors and activators of the SK channel family. The study is timely since inhibitors of SK channels are currently in clinical trials to treat atrial arrhythmias.

Salt bridge

Heterologous expression

10.1073/pnas.2318900121

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Citations (1)

The Piezo channel is a mechano-sensitive complex component in the mammalian inner ear hair cell

Nature Communications (2024)

Jeong Han Lee Maria C. Perez-Flores Seojin Park Hyo Jeong Kim Yingying Chen

Abstract The inner ear is the hub where hair cells (HCs) transduce sound, gravity, and head acceleration stimuli to the brain. Hearing and balance rely on mechanosensation, the fastest sensory signals transmitted to the brain. The mechanoelectrical transducer (MET) channel is the entryway for the sound-balance-brain interface, but the channel-complex composition is not entirely known. Here, we report that the mouse utilizes Piezo1 (Pz1) and Piezo2 (Pz2) isoforms as MET-complex components. The Pz channels, expressed in HC stereocilia, and cell lines are co-localized and co-assembled with MET complex partners. Mice expressing non-functional Pz1 and Pz2 at the ROSA26 locus have impaired auditory and vestibular traits that can only be explained if the Pzs are integral to the MET complex. We suggest that Pz subunits constitute part of the MET complex and that interactions with other MET complex components yield functional MET units to generate HC MET currents.

Stereocilia (inner ear)

mechanosensation

Kinocilium

Mechanotransduction

10.1038/s41467-023-44230-x

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Citations (11)

BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts

Nature Communications (2024)

Maartje Westhoff Silvia G. del Villar Taylor L. Voelker Phung N. Thai Heather C. Spooner

Abstract Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac Ca V 1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca 2+ transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.

Knockout mouse

10.1038/s41467-024-47847-8

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Disruption of mitochondria–sarcoplasmic reticulum microdomain connectomics contributes to sinus node dysfunction in heart failure

Proceedings of the National Academy of Sciences (2022)

Lu Ren Raghavender R. Gopireddy Guy Perkins Hao Zhang Valeriy Timofeyev

The sinoatrial node (SAN), the leading pacemaker region, generates electrical impulses that propagate throughout the heart. SAN dysfunction with bradyarrhythmia is well documented in heart failure (HF). However, the underlying mechanisms are not completely understood. Mitochondria are critical to cellular processes that determine the life or death of the cell. The release of Ca2+ from the ryanodine receptors 2 (RyR2) on the sarcoplasmic reticulum (SR) at mitochondria-SR microdomains serves as the critical communication to match energy production to meet metabolic demands. Therefore, we tested the hypothesis that alterations in the mitochondria-SR connectomics contribute to SAN dysfunction in HF. We took advantage of a mouse model of chronic pressure overload-induced HF by transverse aortic constriction (TAC) and a SAN-specific CRISPR-Cas9-mediated knockdown of mitofusin-2 (Mfn2), the mitochondria-SR tethering GTPase protein. TAC mice exhibited impaired cardiac function with HF, cardiac fibrosis, and profound SAN dysfunction. Ultrastructural imaging using electron microscope (EM) tomography revealed abnormal mitochondrial structure with increased mitochondria-SR distance. The expression of Mfn2 was significantly down-regulated and showed reduced colocalization with RyR2 in HF SAN cells. Indeed, SAN-specific Mfn2 knockdown led to alterations in the mitochondria-SR microdomains and SAN dysfunction. Finally, disruptions in the mitochondria-SR microdomains resulted in abnormal mitochondrial Ca2+ handling, alterations in localized protein kinase A (PKA) activity, and impaired mitochondrial function in HF SAN cells. The current study provides insights into the role of mitochondria-SR microdomains in SAN automaticity and possible therapeutic targets for SAN dysfunction in HF patients.

MFN2

Sarcolemma

Lipid microdomain

Pressure overload

Colocalization

10.1073/pnas.2206708119

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Citations (22)

Publisher Correction: BIN1 knockdown rescues systolic dysfunction in aging male mouse hearts

Nature Communications (2024)

Maartje Westhoff Silvia G. del Villar Taylor L. Voelker Phung N. Thai Heather C. Spooner

10.1038/s41467-024-48944-4

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Cardiac-specific Conditional Knockout of the 18-kDa Mitochondrial Translocator Protein Protects from Pressure Overload Induced Heart Failure

Scientific Reports (2018)

Phung N. Thai Daniel J. Daugherty Bert J. Frederich Xiyuan Lu Wenbin Deng

Abstract Heart failure (HF) is characterized by abnormal mitochondrial calcium (Ca 2+ ) handling, energy failure and impaired mitophagy resulting in contractile dysfunction and myocyte death. We have previously shown that the 18-kDa mitochondrial translocator protein of the outer mitochondrial membrane (TSPO) can modulate mitochondrial Ca 2+ uptake. Experiments were designed to test the role of the TSPO in a murine pressure-overload model of HF induced by transverse aortic constriction (TAC). Conditional, cardiac-specific TSPO knockout (KO) mice were generated using the Cre- lox P system. TSPO-KO and wild-type (WT) mice underwent TAC for 8 weeks. TAC-induced HF significantly increased TSPO expression in WT mice, associated with a marked reduction in systolic function, mitochondrial Ca 2+ uptake, complex I activity and energetics. In contrast, TSPO-KO mice undergoing TAC had preserved ejection fraction, and exhibited fewer clinical signs of HF and fibrosis. Mitochondrial Ca 2+ uptake and energetics were restored in TSPO KO mice, associated with decreased ROS, improved complex I activity and preserved mitophagy. Thus, HF increases TSPO expression, while preventing this increase limits the progression of HF, preserves ATP production and decreases oxidative stress, thereby preventing metabolic failure. These findings suggest that pharmacological interventions directed at TSPO may provide novel therapeutics to prevent or treat HF.

Translocator protein

Pressure overload

Conditional gene knockout

Knockout mouse

10.1038/s41598-018-34451-2

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Citations (41)