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Garcia Caraballo, S.

Publications and source records attributed to Garcia Caraballo, S..

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↗
bioRxiv2020

Activation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension

Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Here we show in mice with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either individually or in combination, with high levels of co-expression with Trpv1 (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In ex vivo bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-cluster{Delta}-/- mice. In vitro whole-cell patch clamp recordings showed that application of an MrgprA3/C11 agonist cocktail induced neuronal hyper-excitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist cocktail into the bladder of wild-type mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK-immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of wild-type, but not Mrgpr-cluster{Delta}-/- mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors is not required for normal bladder function but does trigger hypersensitivity to distension, a critically valuable factor for therapeutic target development. Significance statementDetermining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitisation may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.

neuroscience↗