Biology subjects

Venugopal, S.

Publications and source records attributed to Venugopal, S..

6 recordsLinked to original sources

bioRxiv2026

AKAP5 and Caveolin-1 organize opposing nanodomains that regulate smooth muscle contraction and blood pressure

TRPV4 ion channels in vascular smooth muscle cells (SMCs) are crucial regulators of blood pressure, and their functional effects are differentially shaped by their signaling partners. However, the mechanisms by which TRPV4 channels are compartmentalized into distinct signaling nanodomains with opposite impacts on blood pressure remain unclear. Here, we identify the scaffolding proteins that compartmentalize TRPV4 channels into discrete nanometer-scale signaling domains at the SMC plasma membrane and define how these nanodomains produce opposing effects on vasoconstriction and blood pressure. We show that AKAP5 anchors a nanodomain linking 1-adrenergic receptors, protein kinase C and TRPV4 channels, thereby driving sympathetic vasoconstriction and blood pressure elevation. In contrast, caveolin-1 promotes a mechanosensitive nanodomain comprising Piezo1, TRPV4, and BK channels that mediates vasodilation and a decrease in blood pressure. In hypertension, AKAP5-dependent constrictor nanodomains are hyperactive, whereas caveolin-1-based dilator nanodomains are hypoactive, shifting the balance toward pathological vasoconstriction. These findings reveal fundamental mechanisms that organize smooth muscle TRPV4 channels into spatially and functionally distinct nanodomains regulating blood pressure and show how disruption of this organization contributes to blood pressure elevation in hypertension.

physiology↗

bioRxiv2024

Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is a rare neurometabolic disease caused by mutations in the ABCD1 gene, which encodes for the peroxisomal very long chain fatty acid (VLCFAs) transporter. It is a debilitating disorder, which has a spectrum of clinical presentations. The most severe form is a rapidly progressing demyelinating disease called cerebral ALD or CALD. Patients with cALD have a life expectancy of 2-4 years after onset and symptoms often manifest in childhood. The other forms are adrenomyeloneuropathy or AMN, which is a slower progressing degeneration of the spinal cord, and adrenal insufficiency (Addison disease). Since the accumulation of VLCFAs are a common factor in all ALD pathologies, we identified therapeutic approach that could correct this metabolic defect. We developed a substrate reduction therapy (SRT) for ALD in the form of an inhibitor of the lipid elongase principally responsible for the generation of VLCFAs, Elovl1. This small molecule was able to successfully reduce the accumulation of VLCFA in the brain and spinal cord of ABCD1-/y mice. We used single nuclei RNA seq to identify the pathways altered in the ABCD1-/y mouse and corrected with Elovl1 inhibition. Though many lipid metabolism genes and pathways were indeed corrected, treatment with the Elovl1 inhibitor unexpectedly led to profound transcriptional changes beyond correction of pathways altered by loss of ABCD1. These data suggest that Elovl1 inhibition may have broader consequences in ABCD1-/y mice than correction of lipid homeostasis.

pharmacology and toxicology↗

bioRxiv2021

Diminished GAD67 Terminals and Ambient GABA Inhibition Associated with Reduced Motor Neuron Recruitment Threshold in the SOD1G93A ALS mouse

Pre-symptomatic studies in mouse models of the neurodegenerative motor neuron (MN) disease, Amyotrophic Lateral Sclerosis (ALS) highlight early alterations in intrinsic and synaptic excitability and have supported an excitotoxic theory of MN death. However, a role for synaptic inhibition in disease development is not sufficiently explored among other mechanisms. Since inhibition plays a role in both regulating motor output and in neuroprotection, we examined the age-dependent anatomical changes in inhibitory presynaptic terminals on MN cell bodies using fluorescent immunohistochemistry for GAD67 (GABA) and GlyT2 (glycine) presynaptic proteins comparing ALS-vulnerable trigeminal jaw closer (JC) motor pools with the ALS-resistant extraocular (EO) MNs in the SOD1G93A mouse model for ALS. Our results indicate differential patterns of temporal changes of these terminals in vulnerable versus resilient MNs and relative differences between SOD1G93A and wild-type (WT) MNs. Notably, we found pre-symptomatic up-regulation in inhibitory terminals in the EO MNs while the vulnerable JC MNs mostly showed a decrease in inhibitory terminals. Specifically, there was a statistically significant decrease in the GAD67 somatic abuttal in the SOD1G93A JC MNs compared to WT around P12. Using in vitro patch-clamp electrophysiology, we found a parallel decrease in the ambient GABA-dependent tonic inhibition in the SOD1G93A JC MNs. While it is unclear if the two mechanisms are directly related, pharmacological blockade of specific subtype of GABAA-5 receptors suggests that tonic inhibition can control MN recruitment threshold. Furthermore, reduction in tonic GABA current as observed here in the mutant, identifies a putative molecular mechanism explaining our observations of hyperexcitable shifts in JC MN recruitment threshold in the SOD1G93A mouse. Lastly, we showcase non-parametric resampling-based bootstrap statistics for data analyses, and provide the Python code on GitHub for wider reuse.

neuroscience↗

bioRxiv2021

Engaging Biological Oscillators through Second Messenger Pathways Permits Emergence of a Robust Gastric Slow-Wave during Peristalsis

Peristalsis, the coordinated contraction - relaxation of the muscles of the stomach is important for normal gastric motility and is impaired in motility disorders. Coordinated electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICC) and smooth muscle (SM) cells of the stomach wall as a slow-wave, underly peristalsis. Normally, the gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. Understanding of the integrative role of neurotransmission and intercellular coupling in the propagation of an entrained gastric slow-wave, important for understanding motility disorders, however, remains incomplete. Using a computational framework constituted of a novel gastric motility network (GMN) model we address the hypothesis that engaging biological oscillators (i.e., ICCs) by constitutive gap junction coupling mechanisms and enteric neural stimulus activated signals can confer a robust entrained gastric slow-wave. We demonstrate that while a decreasing enteric neural stimulus gradient that modulates the intracellular IP3 concentration in the ICCs can guide the aboral slow-wave propagation essential for peristalsis, engaging ICCs by recruiting the exchange of second messengers (inositol trisphosphate (IP3) and Ca2+) ensures a robust entrained longitudinal slow-wave, even in the presence of biological variability in coupling strengths. Our GMN with the distinct intercellular coupling in conjunction with the intracellular feedback pathways and a rostrocaudal enteric neural stimulus gradient allows gastric slow waves to oscillate with a moderate range of frequencies and to propagate with a broad range of velocities, thus preventing decoupling observed in motility disorders. Overall, the findings provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach, offer directions for future experiments and theoretical work, and can potentially aid in the design of new interventional pharmacological and neuromodulation device treatments for addressing gastric motility disorders. Author SummaryThe coordinated contraction and relaxation of the muscles of the stomach, known as peristalsis is important for normal gastric motility and primarily governed by electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICCs) and smooth muscle cells of the stomach wall as a slow-wave. Under normal conditions, a gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. However, the understanding of intrinsic and extrinsic mechanisms that ensure propagation of a robust entrained slow-wave remains incomplete. Here, using a computational framework, we show that in conjunction with an enteric neural stimulus gradient along the rostrocaudal ICC chain, and intercellular electrical coupling, the intercellular exchange of inositol trisphosphate between ICCs prevents decoupling by extending the longitudinal entrainment range along the stomach wall, even when variability in intercellular coupling exists. The findings from our study indicate ways that ensure the rostrocaudal spread of a robust gastric slow-wave and provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach.

neuroscience↗

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↗