Biology subjects

Gomez, M. V.

Publications and source records attributed to Gomez, M. V..

3 recordsLinked to original sources

bioRxiv2023

ω-Phonetoxins inhibit voltage-gated calcium CaV2.2 ion channel splice isoforms of dorsal root ganglia

Cell-specific alternative splicing of Cacna1b pre-mRNA generates functionally distinct voltage-gated CaV2.2 channels. CaV2.2 channels mediate the release of glutamate from nociceptor termini in the dorsal horn spinal cord and they are implicated in chronic pain. One alternatively spliced exon in Cacna1b, e37a, is highly expressed in dorsal root ganglia, relative to other regions of the nervous system, and it is particularly important in inflammatory hyperalgesia. Here we studied the effects of two {omega}-phonetoxins, PnTx3-4 and Ph1{beta}, derived from the spider Phoneutria nigriventer on CaV2.2 channel isoforms of dorsal root ganglia (CaV2.2 e37a and CaV2.2 e37b). Both PnTx3-4 and Ph1{beta} are known to have analgesic effects in rodent models of pain and to inhibit CaV2.2 channels. CaV2.2 e37a and CaV2.2 e37b isoforms expressed in a mammalian cell line were inhibited by PnTx3-4 and Ph1{beta} with similar potency and with similar timecourse, although CaV2.2 e37a currents were slightly, but consistently more sensitive to toxin inhibition compared to CaV2.2 e37b. The inhibitory effects of PnTx3-4 and Ph1{beta} on CaV2.2-e37a and CaV2.2-e37b channels were voltage-dependent, and both occlude the inhibitory effects of {omega}-conotoxin GVIA, consistent with a common site of action. The potency of PnTx3-4 and Ph1{beta} on both major splice isoforms in dorsal root ganglia constribute to understanding the analgesic actions of these {omega}-phonetoxins.

neuroscience↗

bioRxiv2022

Holistic profiling of the venom from the lethal spider Phoneutria nigriventer by combining high-throughput ion channel screens with venomics

Spider venoms are a unique source of bioactive peptides, many of which display remarkable biological stability and neuroactivity. Phoneutria nigriventer, often referred to as the Brazilian wandering spider, banana spider or "armed" spider, is endemic to South America and amongst the most dangerous venomous spiders in the world. There are 4,000 envenomation accidents with P. nigriventer each year in Brazil, which can lead to symptoms including priapism, hypertension, blurred vision, sweating, and vomiting. In addition to its clinical relevance, P. nigriventer venom contains peptides that provide therapeutic effects in a range of disease models. In this study, we explored the neuroactivity and molecular diversity P. nigriventer venom using fractionation-guided high-throughput cellular assays coupled to proteomics and multi-pharmacology activity to broaden the knowledge about this venom and its therapeutic potential and provide a proof-of-concept for an investigative pipeline to study spider-venom derived neuroactive peptides. We coupled proteomics with ion channel assays using a neuroblastoma cell line to identify venom compounds that modulate the activity of voltage-gated sodium and calcium channels, as well as the nicotinic acetylcholine receptor. Our data revealed that P. nigriventer venom is highly complex compared to other neurotoxin-rich venoms and contains potent modulators of voltage-gated ion channels which were classified into four families of neuroactive peptides based on their activity and structures. In addition to the reported P. nigriventer neuroactive peptides, we identified at least 27 novel cysteine-rich venom peptides for which their activity and molecular target remains to be determined. Our findings provide a platform for studying the bioactivity of known and novel neuroactive components in the venom of P. nigriventer and other spiders and suggests that our discovery pipeline can be used to identify ion channel-targeting venom peptides with potential as pharmacological tools and to drug leads.

pharmacology and toxicology↗

bioRxiv2017

CLAPO syndrome: Identification of somatic activating PIK3CA mutations and delineation of the natural history and phenotype

BackgroundCLAPO syndrome is a rare vascular disorder characterized by Capillary malformation of the lower lip, Lymphatic malformation predominant on the face and neck, Asymmetry, and Partial/generalized Overgrowth. Although the genetic cause is not known, the tissue distribution of the clinical manifestations in CLAPO seems to follow a pattern of somatic mosaicism.\n\nSubjects and methodsWe clinically evaluated a cohort of 13 patients with CLAPO and screened 20 DNA blood/tissue samples from nine patients using high-throughput, deep sequencing.\n\nResultsWe identified five activating mutations in the PIK3CA gene in affected tissues from six of the nine patients studied; one of the variants (NM_006218.2:c.248T>C; p.Phe83Ser) has not been previously described in developmental disorders.\n\nConclusionsWe describe for the first time the presence of somatic activating PIK3CA mutations in patients with CLAPO. We also report an update of the phenotype and natural history of the syndrome.

genetics↗