Biology subjects

Jones, C. K.

Publications and source records attributed to Jones, C. K..

4 recordsLinked to original sources

bioRxiv2026

Targeting Protease-activated Receptor 4 (PAR4) Protects Against Acute Kidney Injury (AKI) in Ischemia Reperfusion Injury

Acute kidney injury (AKI) is a serious and common clinical syndrome that currently has no effective treatment. Emerging evidence links coagulation pathways to kidney injury, particularly through coagulation proteases. Protease-activated receptors (PARs) are a family of G-protein coupled receptors (GPCRs) that are activated by proteolytic cleavage of their N termini, exposing a tethered ligand that initiates receptor signaling. PARs have been shown to play a major role in inflammation, vascular regulation, and tissue injury. PARs play key roles in inflammation, vascular regulation, and tissue injury. Previous work from the Hamm laboratory demonstrated that PAR4 contributes to AKI progression, as PAR4 knockout mice were protected in both unilateral ureteral obstruction and ischemia-reperfusion-based models of kidney disease. In this study, we investigated the potential of a PAR4 antagonist, VU6073819, at mitigating AKI progression in an ischemia-reperfusion injury (IRI) mouse model. PAR4 antagonism not only alleviated kidney injury and inflammatory response, but it significantly improved the survival. These findings identify PAR4 as a promising therapeutic target for AKI.

pharmacology and toxicology↗

bioRxiv2025

Identification of M4 muscarinic acetylcholine receptor expressing astrocytes that regulate locomotion and survival in murine prion disease

Whilst there has been much focus on neuronally expressed muscarinic acetylcholine receptors (mAChRs), less attention has been paid to their expression and role in non-neuronal brain cells. Using genetically engineered mice, we identify a previously unappreciated subpopulation of astrocytes expressing the M4 mAChR subtype dispersed across various regions that include the brainstem, hypothalamus and, most abundantly, the cerebellum. Signalling and proteomic analysis of M4 mAChR positive astrocytes from the cerebellum confirmed functional receptor expression and its role in regulating protein expression. Genetic ablation of these astrocytes in mice revealed a specific role in locomotion. Importantly, in the context of murine prion disease, we observed a significant expansion of M4 mAChR positive astrocytes, and ablation experiments established that this astrocyte subpopulation has a detrimental effect on late-stage disease. Together we identify M4 mAChR expressing astrocyte subpopulation that plays a specific role in normal neurophysiology and the progression of inflammatory neurodegenerative disease.

neuroscience↗

bioRxiv2022

M1 selective muscarinic allosteric modulation enhances cognitive flexibility and effective salience in nonhuman primates

Acetylcholine (ACh) in cortical neural circuits mediates how selective attention is sustained in the presence of distractors and how flexible cognition adjusts to changing task demands. The cognitive domains of attention and cognitive flexibility might be differentially supported by the M1 muscarinic cholinergic sub-receptor. Understanding how M1 mechanisms support these cognitive subdomains is of highest importance for advancing novel drug treatments for conditions with altered attention and reduced cognitive control including Alzheimers disease or schizophrenia. Here, we tested this question by assessing how the subtype selective M1-receptor specific positive allosteric modulator (M1 PAM VU0453595) affects visual search and flexible reward-learning in nonhuman primates. We found that allosteric potentiation of the M1 receptor enhanced flexible learning performance by improving extra-dimensional set shifting, by reducing latent inhibition of previously experienced distractors, and by reducing response perseveration in the absence of adverse side effects. These pro-cognitive effects occurred in the absence of apparent changes of attentional performance during visual search. In contrast, non-selective ACh modulation using the acetylcholinesterase inhibitor donepezil improved attention during visual search at doses that did not alter cognitive flexibility and that already triggered gastrointestinal cholinergic side effects. These findings illustrate that M1 positive allosteric modulation enhances cognitive flexibility without affecting attentional filtering of distraction, consistent with M1 activity boosting the effective salience of relevant over irrelevant objects. These results suggest that M1 PAMs are versatile compounds for enhancing cognitive flexibility in disorders spanning schizophrenia and Alzheimers diseases. Statement of significanceMuscarinic receptors mediate the pro-cognitive effects of acetylcholine, but it has remained unclear whether they differentially affect the cognitive subfunctions of attentional filtering, set shifting, and learning. To clarify the functional specificity of M1 receptors, we assessed these diverse functions using a recently developed, highly selective M1 PAM. This M1 PAM caused domain-specific cognitive improvement of flexible learning and extra-dimensional set shifting, reduced perseverations and enhanced target recognition during learning without altering attentional filtering functions. These domain-specific improvement contrasted to effects of a non-selective acetylcholinesterase inhibitor that primarily enhanced attention and caused dose limiting adverse side effects. These results demonstrate domain-specific improvements of cognitive flexibility suggesting M1 PAMs are versatile compounds for treating cognitive deficits in schizophrenia and Alzheimers disease.

neuroscience↗

bioRxiv2018

Disabling Gβγ SNARE interaction in transgenic mice disrupts GPCR-mediated presynaptic inhibition leading to physiological and behavioral phenotypes.

Gi/o-coupled G-protein coupled receptors modulate neurotransmission presynaptically through inhibition of exocytosis. Release of G{beta}{gamma} subunits decreases the activity of voltage-gated calcium channels (VGCC), decreasing excitability. A less understood G{beta}{gamma}-mediated mechanism downstream of calcium entry is the binding of G{beta}{gamma} to SNARE complexes. Here, we create a mouse partially deficient in this interaction. SNAP25{Delta}3 homozygote animals are developmentally normalbut impaired gait and supraspinal nociception. They also have elevated stress-induced hyperthermia and impaired inhibitory postsynaptic responses to 2A-AR, but normal inhibitory postsynaptic responses to Gi/o-coupled GABAB receptor activation. SNAP25{Delta}3 homozygotes have deficits in inhibition of hippocampal postsynaptic responses to 5 HT1b agonists that affect hippocampal learning. These data suggest that Gi/o-coupled GPCR inhibition of exocytosis through the G{beta}{gamma}-SNARE interaction is a crucial component of numerous physiological and behavioral processes.

neuroscience↗