Biology subjects

Peters, C. J.

Publications and source records attributed to Peters, C. J..

4 recordsLinked to original sources

bioRxiv2026

Conformational changes upon pore blocker removal reveal conductive states of TMEM16A

TMEM16A is a Ca2+-activated anion channel that provides direct electrical feedback to the plasma membrane in response to intracellular Ca2+. Its conductive state remains unresolved, leaving questions about gating, Cl- permeation, and modulation by Ca2+, depolarization, and lipids. To investigate the open state, we performed molecular dynamics simulations of TMEM16A bound to the putative open-state blocker 1PBC. After inhibitor removal, the putative, pore-lining helix TM4 developed kinks at two sites: an upper site that opens the pore for Cl- permeation, and a deeper site causing constriction. A conserved hydrophobic network between TM3 and TM4 persisted in most open structures but separated during extreme dilation, allowing lipids to transiently block the pore. Patch-clamp recordings indicated that the intact network promotes activation. Further simulations yielded >60 Cl- permeation events and a single-channel conductance matching experiments. Additional electrostatic and kinetic modeling indicated that TMEM16As transition from outward-rectification to Ohmic conductance with increasing Ca2+ results from a weak voltage dependence of Ca2+ binding, which act cooperatively to open the pore. HIGHLIGHTSO_LIRemoval of the inhibitor 1PBC from TMEM16A induces spontaneous transitions to ion conductive and non-conductive states via bending in TM4 at two different locations. C_LIO_LISimulations suggest that the open state is stabilized by a small hydrophobic network between TM3 and 4 and disrupting this network biases channel closure in electrophysiological recordings. C_LIO_LIA kinetic model of conduction based on energetics from the all-atom MD simulations coupled to continuum calculations gives a linear current-voltage curve consistent with the fully open conformation and removal of 1 Ca2+ switches to an outwardly rectifying state via electrostatic influence on the Cl- energy profile. However, the rectification is too weak to match experiment, but a cooperative model of Ca2+ binding with weak voltage-dependence does match experiment. C_LI

biophysics↗

bioRxiv2025

Presynaptic GABAB autoreceptors suppress neurotransmitter release during repetitive stimulation via the Gβγ-SNARE pathway.

GABAergic signaling provides the brains primary inhibitory mechanism with defects linked to epilepsy, anxiety, depression, insomnia, schizophrenia and neurodegeneration. A key regulatory mechanism is autoinhibition of GABA release during repetitive activity via presynaptic Gi/o-coupled GABAB receptors, supporting synaptic tuning and memory formation, and limiting neurotransmitter spillover. Exogenous GABAB receptor agonists reduce presynaptic Ca2+ entry by inhibiting calcium channels. However, using transgenic mice expressing a mutant SNAP25 with diminished ability to bind G{beta}{gamma} (SNAP25{Delta}3), we show that suppression by GABAB autoreceptors requires intact G{beta}{gamma}-SNARE interactions. Imaging of presynaptic Ca2+ transients in GABAergic axons showed no GABA-mediated autoreceptor suppression of Ca2+ entry during stimulus trains. In contrast, application of the exogenous GABAB receptor agonist baclofen profoundly inhibited Ca2+ entry, which could be partially reversed by exogenously elevating cAMP, indicating a complementary role of inhibition of adenylyl cyclase. Baclofen reduced spontaneous IPSC frequency and amplitude and both effects were diminished in SNAP25{Delta}3 mice, consistent with inhibition at Ca2+ channels and SNARE complexes. Physiological GABA-mediated and exogenous GABAB receptor activation thus produce distinct outcomes on GABAergic neurotransmission, indicating that synthetic drug application to neurons does not faithfully recapitulate endogenous signaling pathways. We conclude that endogenous rapid GABAB autoreceptor signaling inhibits neurotransmitter release primarily by G{beta}{gamma}-mediated inhibitions of SNARE mechanisms, whereas prolonged agonist application additionally suppresses Ca2+ influx via cAMP signaling.

neuroscience↗

bioRxiv2024

Chemogenetic control of GABAergic activity within the interpeduncular nucleus reveals dissociable behavioral components of the nicotine withdrawal phenotype

Chronic exposure to nicotine results in the development of a dependent state such that a withdrawal syndrome is elicited upon cessation of nicotine. The habenulo-interpeduncular (Hb-IPN) circuit contains a high concentration of nAChRs and has been identified as a main circuit involved in nicotine withdrawal. Here we investigated the contribution of two distinct subpopulations of IPN GABAergic neurons to nicotine withdrawal behaviors. Using a chemogenetic approach to specifically target Amigo1-expressing or Epyc-expressing neurons within the IPN, we found that activity of the Amigo1 and not the Epyc subpopulation of GABAergic neurons is critical for anxiety-like behaviors both in naive mice and in those undergoing nicotine withdrawal. Moreover, data revealed that stimulation of Amigo1 neurons in nicotine-naive mice elicits opposite effects on affective and somatic signs of withdrawal. Taken together, these results suggest that somatic and affective behaviors constitute dissociable components of the nicotine withdrawal phenotype and are likely supported by distinct subpopulations of neurons within the IPN.

neuroscience↗

bioRxiv2019

Paralytic, the Drosophila voltage-gated sodium channel, regulates proliferation of neural progenitors

Proliferating cells, typically considered \"non-excitable,\" nevertheless exhibit regulation by bioelectrical signals. Notably, voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability, are also found in progenitors and upregulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic (para), the sole gene that encodes Drosophila VGSC, reduces neuroblast progeny cell number. The type II neuroblast lineages, featuring a transit-amplifying intermediate neural progenitors (INP) population similar to that found in the developing human cortex, are particularly sensitive to para manipulation. Following a series of asymmetric divisions, INPs normally exit the cell cycle through a final symmetric division. Our data suggests that loss of para induces apoptosis in this population, whereas overexpression leads to an increase in INPs and overall neuroblast progeny cell numbers. These effects are cell autonomous and depend on Para channel activity. Reduction of Para not only affects normal NB development, but also strongly suppresses brain tumor mass, implicating a role for Para in cancer progression. To our knowledge, our studies are the first to identify a role for VGSC in neural progenitor proliferation. Elucidating the contribution of VGSC in proliferation will advance our understanding of bioelectric signaling within development and disease states.

developmental biology↗