Biology subjects

Olcese, R.

Publications and source records attributed to Olcese, R..

5 recordsLinked to original sources

bioRxiv2024

A rich conformational palette underlies human CaV2.1-channel availability

Depolarization-evoked opening of CaV2.1 (P/Q-type) Ca2+-channels triggers neurotransmitter release, while voltage-dependent inactivation (VDI) limits channel availability to open, contributing to synaptic plasticity. The mechanism of CaV2.1 response to voltage is unclear. Using voltage-clamp fluorometry and kinetic modeling, we optically tracked and physically characterized the structural dynamics of the four CaV2.1 voltage-sensor domains (VSDs). VSD-I seems to directly drive opening and convert between two modes of function, associated with VDI. VSD-II is apparently voltage-insensitive. VSD-III and VSD-IV sense more negative voltages and undergo voltage-dependent conversion uncorrelated with VDI. Auxiliary {beta}-subunits regulate VSD-I-to-pore coupling and VSD conversion kinetics. CaV2.1 VSDs are differentially sensitive to voltage changes brief and long-lived. Specifically the voltage-dependent conformational changes of VSD-I are linked to synaptic release and plasticity.

neuroscience↗

bioRxiv2024

Electrical and G-protein Regulation of CaV2.2 (N-type) Channels

How G-proteins inhibit N-type, voltage-gated, calcium-selective channels (CaV2.2) during presynaptic inhibition is a decades-old question. G-proteins G{beta}{gamma} bind to intracellular CaV2.2 regions, but the inhibition is voltage-dependent. Using the hybrid electrophysiological and optical approach voltage-clamp fluorometry, we show that G{beta}{gamma} acts by selectively inhibiting a subset of the four different CaV2.2 voltage-sensor domains (VSDs I-IV). During regular "willing" gating, VSDs I and IV activation resemble pore opening, VSD III activation is hyperpolarized, and VSD II appears unresponsive to depolarization. In the presence of G{beta}{gamma}, CaV2.2 gating is "reluctant": pore opening and VSD-I activation are strongly and proportionally inhibited, VSD IV is modestly inhibited while VSD III is not. We propose that G{beta}{gamma} inhibition of VSD-I and -IV underlies reluctant CaV2.2 gating and subsequent presynaptic inhibition.

neuroscience↗

bioRxiv2024

Decreased Left Atrial Cardiomyocyte FGF13 Expression Increases Vulnerability to Postoperative Atrial Fibrillation in Humans

Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery and a significant cause of increased morbidity and mortality. The development of novel POAF therapeutics has been limited by an insufficient understanding of molecular mechanisms promoting atrial fibrillation. In this observational cohort study, we enrolled 28 patients without a history of atrial fibrillation that underwent mitral valve surgery for degenerative mitral regurgitation and obtained left atrial tissue samples along the standard atriotomy incision in proximity to the right pulmonary veins. We isolated cardiomyocytes and performed transcriptome analyses demonstrating 13 differentially expressed genes associated with new-onset POAF. Notably, decreased expression of fibroblast growth factor 13 (FGF13), a fibroblast growth factor homologous factor known to modulate voltage-gated sodium channel NaV1.5 inactivation, had the most significant association with POAF. To assess the functional significance of decreased FGF13 expression in atrial myocytes, we performed patch clamp experiments on neonatal rat atrial myocytes after siRNA-mediated FGF13 knockdown, demonstrating action potential prolongation. These critical findings indicate that decreased FGF13 expression promotes vulnerability to POAF.

genomics↗

bioRxiv2019

Circuit-Specific Early Impairment of Proprioceptive Sensory Neurons in the SOD1G93A Mouse Model for ALS

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease in which motor neurons degenerate resulting in muscle atrophy, paralysis and fatality. Studies using mouse models of ALS indicate a protracted period of disease development with progressive motor neuron pathology, evident as early as embryonic and postnatal stages. Key missing information includes concomitant alterations in the sensorimotor circuit essential for normal development and function of the neuromuscular system. Leveraging unique brainstem circuitry, we show in vitro evidence for reflex circuit-specific postnatal abnormalities in the jaw proprioceptive sensory neurons in the well-studied SOD1G93A mouse. These include impaired and arrhythmic action potential burst discharge associated with a deficit in Nav1.6 Na+ channels. However, the mechanoreceptive and nociceptive trigeminal ganglion neurons and the visual sensory retinal ganglion neurons were resistant to excitability changes in age matched SOD1G93A mice. Computational modeling of the observed disruption in sensory patterns predicted asynchronous self-sustained motor neuron discharge suggestive of imminent reflexive defects such as muscle fasciculations in ALS. These results demonstrate a novel reflex circuit-specific proprioceptive sensory abnormality in ALS.\n\nSignificance StatementNeurodegenerative diseases have prolonged periods of disease development and progression. Identifying early markers of vulnerability can therefore help devise better diagnostic and treatment strategies. In this study, we examined postnatal abnormalities in the electrical excitability of muscle spindle afferent proprioceptive neurons in the well-studied SOD1G93A mouse model for neurodegenerative motor neuron disease, ALS. Our findings suggest that these proprioceptive sensory neurons are exclusively afflicted early in the disease process relative to sensory neurons of other modalities. Moreover, they presented Nav1.6 Na+ channel deficiency which contributed to arrhythmic burst discharge. Such sensory arrhythmia could initiate reflexive defects such as muscle fasciculations in ALS as suggested by our computational model.

neuroscience↗

bioRxiv2018

A Mechanism of Real-Time Noise Modulation in Neurons

Uncertainties pose an ongoing challenge for information processing in the nervous system. It is not entirely clear how neurons maintain dynamic stability of information, encoded in the temporal features of spike trains, notwithstanding stochastic influences. Here we examined the contribution of subclasses of membrane sodium currents in real-time noise modulation in sensory neurons. Fast sodium (Na+) currents are essential for spike generation, and a persistent Na+ current can entrain preferred input frequencies via membrane resonance. Using mathematical modeling, theory and experiments, we show that a resurgent Na+ current can stabilize the temporal features of burst discharge and confer noise tolerance. These novel insights reckon the role of biophysical properties of Na+ currents beyond mere spike generation. Instead, these mechanisms might be how neurons perform real-time signal processing to maintain order and entropy in neural discharge. Our model analysis further predicts a negative feedback loop in the molecular machinery of an underlying Nav1.6-type Na+ channel gating considered in this study.

neuroscience↗