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Brizuela, M.

Publications and source records attributed to Brizuela, M..

2 recordsLinked to original sources
bioRxiv2025

Contribution of CaV2.2 and GIRK1/2 channels to membrane excitability of rodent and human dorsal root ganglion neurons

Chronic visceral pain is a key symptom of irritable bowel syndrome (IBS). Modulation of voltage-dependent calcium and potassium channels by G protein-coupled receptors (GPCRs) plays a key role in dampening nociceptive transmission. Baclofen and the analgesic peptide -conotoxin Vc1.1 both activate GABAB receptors (GABABR), resulting in the inhibition of CaV2.2 and CaV2.3 calcium channels to reduce colonic nociception. Recent studies have also shown that GABABR activation potentiates GIRK1/2 potassium channels in mammalian sensory afferent neurons. In this study, we investigated the expression of these ion channel targets in rodent and human dorsal root ganglion (DRG) neurons, including those innervating the colon. We also examined how CaV2.2 and GIRK channel antagonists, as well as a GIRK channel activator, affect the passive and active electrical properties of adult mouse DRG neurons. Additionally, we assessed the effects of -conotoxin Vc1.1 on neuronal excitability in the presence of the selective CaV2.2 antagonist {omega}-conotoxin CVIE and the GIRK channel activator ML297. We further evaluated the impact of the GIRK channel antagonist Tertiapin-Q on excitability in mouse colonic DRGs and colonic afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating membrane excitability of colonic DRGs. Our findings demonstrate that both CaV2.2 inhibition and GIRK channel potentiation reduce excitability in mouse DRGs, likely mediating the analgesic effects of Vc1.1 and baclofen observed in vivo. However, our findings indicate that GIRK channel potentiation appears to play a limited role in modulating excitability in colon-innervating DRGs and colonic afferents. These findings suggest that neurons innervating different regions of the body employ distinct mechanisms to regulate neuronal excitability and nociceptive signaling. KEY POINTS SUMMARYO_LIGABABR1, CaV2.2, and GIRK1 are highly expressed in the thoracolumbar dorsal root ganglia (DRGs) of both mice and humans. C_LIO_LIIn mouse DRGs, CaV2.2 inhibition and GIRK channel potentiation contribute to reduced neuronal excitability. C_LIO_LIThe analgesic peptide, -conotoxin Vc1.1 reduces neuronal excitability by inhibiting CaV2.2 and potentiating GIRK channels. C_LIO_LIHowever, potentiation of GIRK channels does not significantly affect the excitability in colon-innervating DRG neurons or colonic afferents. C_LIO_LISensory neurons innervating different body regions utilize distinct mechanisms to regulate their excitability. C_LI

neuroscience↗
bioRxiv2022

Gut Enterochromaffin Cells are Critical Drivers of Visceral Pain and Anxiety

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents a significant component of chronic visceral pain 1. For the growing population afflicted by irritable bowel syndrome (IBS), GI hypersensitivity and pain persist long after signs of tissue injury have resolved 2. IBS also exhibits a strong sex bias afflicting women three-fold more than men 1. Identifying the molecules, cells, and circuits that mediate both the acute and persistent phases of visceral pain is a critical first step in understanding how environmental and endogenous factors produce long-term changes in the nervous system or associated tissues to engender chronic pain syndromes 3,4. Enterochromaffin (EC) cells within the gut epithelium are exceedingly rare sensory neuroendocrine cells that detect and transduce noxious stimuli to nearby nerve endings via serotonin. Here, we manipulate murine EC cell activity using genetic strategies to ascertain their contributions to visceral pain. We show that acute EC cell activation is sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterially derived short-chain fatty acid irritant associated with inflammatory GI disorders. Remarkably, prolonged EC cell activation by itself is sufficient to produce persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Perturbing the activity of these rare EC cells led to a marked increase in anxiety-like behaviors that normalized after blocking serotonergic signaling. Sex differences were also observed accross a range of assays indicating that females have a higher baseline visceral sensitivity. Our findings validate a critical role for EC cell-mucosal afferent signaling in acute and persistent GI pain while highlighting mechanistically defined genetic models for studying visceral hypersensitivity, sex differences, and associated behaviors.

physiology↗