ORCID Profile
0000-0002-7447-1310
Current Organisation
Princeton University
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Publisher: Springer Science and Business Media LLC
Date: 30-11-2022
DOI: 10.1038/S41467-022-35026-6
Abstract: The R-type voltage-gated Ca 2+ (Ca v ) channels Ca v 2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson’s disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Ca v 2.3 in complex with α2δ−1 and β3 subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Ca v 2.2, with VSD II in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSD II and the tightly closed pore domain. We also determined the cryo-EM structure of a Ca v 2.3 mutant in which a Ca v 2-unique cytosolic helix in repeat II (designated the CH2 II helix) is deleted. This mutant, named ΔCH2, still reserves a down VSD II , but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and ΔCH2 Ca v 2.3 show that the CH2 II helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2 II helix is not necessary for locking the down state of VSD II .
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-03-2019
DOI: 10.1097/J.PAIN.0000000000001567
Abstract: Pain is the leading cause of disability in the developed world but remains a poorly treated condition. Specifically, postsurgical pain continues to be a frequent and undermanaged condition. Here, we investigate the analgesic potential of pharmacological Na V 1.7 inhibition in a mouse model of acute postsurgical pain, based on incision of the plantar skin and underlying muscle of the hind paw. We demonstrate that local and systemic treatment with the selective Na V 1.7 inhibitor μ-theraphotoxin-Pn3a is effectively antiallodynic in this model and completely reverses mechanical hypersensitivity in the absence of motor adverse effects. In addition, the selective Na V 1.7 inhibitors ProTx-II and PF-04856264 as well as the clinical candidate CNV1014802 also reduced mechanical allodynia. Interestingly, co-administration of the opioid receptor antagonist naloxone completely reversed analgesic effects of Pn3a, indicating an involvement of endogenous opioids in the analgesic activity of Pn3a. In addition, we found superadditive antinociceptive effects of subtherapeutic Pn3a doses not only with the opioid oxycodone but also with the GABA B receptor agonist baclofen. Transcriptomic analysis of gene expression changes in dorsal root ganglia of mice after surgery did not reveal any changes in mRNA expression of endogenous opioids or opioid receptors however, several genes involved in pain, including Runx1 (Runt related transcription factor 1), Cacna1a (Ca V 2.1), and Cacna1b (Ca V 2.2), were downregulated. In summary, these findings suggest that pain after surgery can be successfully treated with Na V 1.7 inhibitors alone or in combination with baclofen or opioids, which may present a novel and safe treatment strategy for this frequent and poorly managed condition.
Publisher: American Chemical Society (ACS)
Date: 19-02-2020
Publisher: Proceedings of the National Academy of Sciences
Date: 07-02-2022
Abstract: The targeting of mammalian ErbB receptor signaling by a venom toxin to cause hypersensitivity is a mode of action that has not previously been described. Natural selection of a defensive toxin to target ErbB signaling provides compelling independent evidence for a fundamental role of this receptor and its ligands in mammalian pain. The evolution of a toxin in ant venom to mimic a vertebrate nociceptive hormone serves as an ex le of both convergent evolution and molecular mimicry, illustrating how natural selection can shape the gene product of one organism to resemble that of another.
Publisher: University of Queensland Library
Date: 2020
DOI: 10.14264/DA5597E
Publisher: MDPI AG
Date: 11-02-2021
DOI: 10.3390/MD19020106
Abstract: The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly (p 0.0001, p 0.0001, and p 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA (p 0.0001, p 0.01, and p 0.05, respectively), and 300 nM and 100 nM GVIA (p 0.0001 and p 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED50 of GVIA and MVIIA in OIPN was found to be 1.8 pmol aw and 0.8 pmol aw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.
Publisher: Elsevier BV
Date: 2021
Publisher: SAGE Publications
Date: 12-11-2017
Abstract: Retrograde fluorescent labeling of dental primary afferent neurons (DPANs) has been described in rats through crystalline fluorescent DiI, while in the mouse, this technique was achieved with only Fluoro-Gold, a neurotoxic fluorescent dye with membrane penetration characteristics superior to the carbocyanine dyes. We reevaluated this technique in the rat with the aim to transfer it to the mouse because comprehensive physiologic studies require access to the mouse as a model organism. Using conventional immunohistochemistry, we assessed in rats and mice the speed of axonal dye transport from the application site to the trigeminal ganglion, the numbers of stained DPANs, and the fluorescence intensity via 1) conventional crystalline DiI and 2) a novel DiI formulation with improved penetration properties and staining efficiency. A 3-dimensional reconstruction of an entire trigeminal ganglion with 2-photon laser scanning fluorescence microscopy permitted visualization of DPANs in all 3 isions of the trigeminal nerve. We quantified DPANs in mice expressing the farnesylated enhanced green fluorescent protein (EGFPf) from the transient receptor potential cation channel subfamily M member 8 (TRPM8
Publisher: Frontiers Media SA
Date: 27-06-2019
Publisher: Elsevier BV
Date: 11-2020
Publisher: Proceedings of the National Academy of Sciences
Date: 24-01-2022
Abstract: Pain development and discomfort are universal features of spider envenomation, yet severe pain arising from bites by Old World spiders is poorly understood. Molecular analyses of the venom of the King Baboon spider revealed abundant expression of the inhibitory cystine knot peptide Pm1a. Synthetic Pm1a induces pain in mice while simultaneously enhancing proexcitatory sodium currents and decreasing inhibitory potassium currents. These concomitant effects promote hyperexcitability in pain-sensing neurons that can be reversed by pharmacological inhibition of voltage-gated sodium channels. The coordinated modulation of excitatory and inhibitory ion channels involved in pain propagation may represent an economical and effective defense strategy in pain-inducing defensive venoms.
Publisher: Rockefeller University Press
Date: 03-03-2021
DOI: 10.1084/JEM.20201452
Abstract: Vincristine is an important component of many regimens used for pediatric and adult malignancies, but it causes a dose-limiting sensorimotor neuropathy for which there is no effective treatment. This study aimed to delineate the neuro-inflammatory mechanisms contributing to the development of mechanical allodynia and gait disturbances in a murine model of vincristine-induced neuropathy, as well as to identify novel treatment approaches. Here, we show that vincristine-induced peripheral neuropathy is driven by activation of the NLRP3 inflammasome and subsequent release of interleukin-1β from macrophages, with mechanical allodynia and gait disturbances significantly reduced in knockout mice lacking NLRP3 signaling pathway components, or after treatment with the NLRP3 inhibitor MCC950. Moreover, treatment with the IL-1 receptor antagonist anakinra prevented the development of vincristine-induced neuropathy without adversely affecting chemotherapy efficacy or tumor progression in patient-derived medulloblastoma xenograph models. These results detail the neuro-inflammatory mechanisms leading to vincristine-induced peripheral neuropathy and suggest that repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.NEUROPHARM.2017.04.014
Abstract: Toxins and venom components that target voltage-gated sodium (Na
Publisher: Springer Science and Business Media LLC
Date: 23-05-2023
DOI: 10.1038/S41467-023-38839-1
Abstract: Stings of certain ant species (Hymenoptera: Formicidae) can cause intense, long-lasting nociception. Here we show that the major contributors to these symptoms are venom peptides that modulate the activity of voltage-gated sodium (Na V ) channels, reducing their voltage threshold for activation and inhibiting channel inactivation. These peptide toxins are likely vertebrate-selective, consistent with a primarily defensive function. They emerged early in the Formicidae lineage and may have been a pivotal factor in the expansion of ants.
Publisher: Elsevier BV
Date: 04-2020
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.JPAIN.2019.06.008
Abstract: Vincristine, oxaliplatin, and cisplatin are commonly prescribed chemotherapeutic agents for the treatment of many tumors. However, a main side effect is chemotherapy-induced peripheral neuropathy (CIPN), which may lead to changes in chemotherapeutic treatment. Although symptoms associated with CIPN are recapitulated by mouse models, there is limited knowledge of how these drugs affect the expression of genes in sensory neurons. The present study carried out a transcriptomic analysis of dorsal root ganglia following vincristine, oxaliplatin, and cisplatin treatment with a view to gain insight into the comparative pathophysiological mechanisms of CIPN. RNA-Seq revealed 368, 295, and 256 differential expressed genes induced by treatment with vincristine, oxaliplatin, and cisplatin, respectively, and only 5 shared genes were dysregulated in all 3 groups. Cell type enrichment analysis and gene set enrichment analysis showed predominant effects on genes associated with the immune system after treatment with vincristine, while oxaliplatin treatment affected mainly neuronal genes. Treatment with cisplatin resulted in a mixed gene expression signature. PERSPECTIVE: These results provide insight into the recruitment of immune responses to dorsal root ganglia and indicate enhanced neuroinflammatory processes following administration of vincristine, oxaliplatin, and cisplatin. These gene expression signatures may provide insight into novel drug targets for treatment of CIPN.
Publisher: Elsevier BV
Date: 04-2017
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-09-2018
Abstract: Characterization of the venom of an ant reveals a erse and multifunctional hymenopteran toxin superfamily.
Publisher: Elsevier BV
Date: 10-2021
No related grants have been discovered for Alexander Mueller.