T-type calcium channels contribute to colonic hypersensitivity in a rat model of irritable bowel syndrome

Abstract

The symptoms of irritable bowel syndrome (IBS) include significant abdominal pain and bloating. Current treatments are empirical and often poorly efficacious, and there is a need for the development of new and efficient analgesics aimed at IBS patients. T-type calcium channels have previously been validated as a potential target to treat certain neuropathic pain pathologies. Here we report that T-type calcium channels encoded by the Ca V 3.2 isoform are expressed in colonic nociceptive primary afferent neurons and that they contribute to the exaggerated pain perception in a butyratemediated rodent model of IBS. Both the selective genetic inhibition of Ca V 3.2 channels and pharmacological blockade with calcium channel antagonists attenuates IBS-like painful symptoms. Mechanistically, butyrate acts to promote the increased insertion of Ca V 3.2 channels into primary sensory neuron membranes, likely via a posttranslational effect. The butyrate-mediated regulation can be recapitulated with recombinant Ca V 3.2 channels expressed in HEK cells and may provide a convenient in vitro screening system for the identification of T-type channel blockers relevant to visceral pain. These results implicate T-type calcium channels in the pathophysiology of chronic visceral pain and suggest Ca V 3.2 as a promising target for the development of efficient analgesics for the visceral discomfort and pain associated with IBS.analgesia | visceral nociceptor | sensitization | trafficking I rritable bowel syndrome (IBS) is one of the most prevalent lower gastrointestinal (GI) tract disorders, affecting ∼20% of the population in developed countries. Despite high prevalence and considerable impairment of quality of life, current treatments for IBS are empirical and often poorly effective, and the disorder remains a challenge to clinicians (1). IBS is characterized by abdominal pain and discomfort associated with abnormal bowel functions. Although different etiologies have been proposed, it is generally accepted that IBS is multifactorial and that there are likely multiple molecular targets relevant to innovative drug development strategies (2). Among these, there is considerable interest in dysregulation of the brain-gut pain neuraxis and specific subtypes of ion channels in primary afferent neurons that mediate the detection of nociceptive stimuli and transmission to the CNS (3). Moreover, in a number of animal models of chronic pain, the pathological remodeling of ion channel expression patterns has been linked to the hyperexcitability of primary afferent nociceptors (4, 5).A number of ionic conductances contribute to neuronal firing, including voltage-gated calcium channels, which uniquely both shape action potentials and influence neuronal excitability. In mammals, 10 pore-forming calcium channel α 1 subunit genes have been identified, three of which, Ca V 3.1, Ca V 3.2, and Ca V 3.3, form low-voltage-activated (LVA) T-type calcium channels that are activated by weak depolarizations and generally act to control excitability (6, 7). Al...

Colonic Hydrogen Sulfide^|^ndash;Induced Visceral Pain and Referred Hyperalgesia Involve Activation of Both Cav3.2 and TRPA1 Channels in Mice

“…These findings are in agreement with the recent evidence that Ca v 3.2, among the three isoforms of T-type Ca 2+ channels, in the sensory neurons plays a major role in processing of somatic (11) and visceral pain (12). Previously, we have shown that luminal H 2 S-induced colonic pain / referred hyperalgesia is prevented by pretreatment with zinc chloride (ZnCl 2 ) and that luminal zinc chelators mimic the T-type Ca 2+ channel-dependent colonic pain / referred hyperalgesia caused by H 2 S (13).…”

Voltage-Gated Calcium Channel Antagonists: Potential Analgesics for Jejunal Pains

“…Stimulation of T-type calcium channels, subtype Ca v 3.2 on the primary signaling visceral afferents was associated with symptoms similar to the irritable bowel syndrome in the animal model. Behavioral symptoms resolved after the application of T-type calcium channels inhibitor [44]. Afferent transduction from mesentery in the experimental intestinal ischaemia was blocked by nifedipine, an L-type calcium channels inhibitor [45].…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Therefore, enhancement of Ca V 3.2 channel expression/activity contributes to pain hypersensitivity. Although no mutations in Ca V 3.2 that result in increased pain in humans have been reported in the literature, peripheral nerve injury or inflammation (Jagodic et al, 2008;García-Caballero et al, 2014), diabetes (Jagodic et al, 2007;Messinger et al, 2009), and colonic inflammation (Marger et al, 2011a) all give rise to increased DRG neuron T-type calcium currents in rodents. At least two mechanisms appear to contribute to this phenomenon: an enhancement of Ca V 3.2 channel trafficking, due to glycosylation in the case of diabetic pain (Orestes et al, 2013;Weiss et al, 2013), and stabilization of these channels as a result of enhanced deubiquitination (García-Caballero et al, 2014).…”