Targeting ion channels for the treatment of gastrointestinal motility disorders

Abstract

Gastrointestinal (GI) functional and motility disorders are highly prevalent and responsible for long-term morbidity and sometimes mortality in the affected patients. It is estimated that one in three persons has a GI functional or motility disorder. However, diagnosis and treatment of these widespread conditions remains challenging. This partly stems from the multisystem pathophysiology, including processing abnormalities in the central and peripheral (enteric) nervous systems and motor dysfunction in the GI wall. Interstitial cells of Cajal (ICCs) are central to the generation and propagation of the cyclical electrical activity and smooth muscle cells (SMCs) are responsible for electromechanical coupling. In these and other excitable cells voltage-sensitive ion channels (VSICs) are the main molecular units that generate and regulate electrical activity. Thus, VSICs are potential targets for intervention in GI motility disorders. Research in this area has flourished with advances in the experimental methods in molecular and structural biology and electrophysiology. However, our understanding of the molecular mechanisms responsible for the complex and variable electrical behavior of ICCs and SMCs remains incomplete. In this review, we focus on the slow waves and action potentials in ICCs and SMCs. We describe the constituent VSICs, which include voltagegated sodium (Na V ), calcium (Ca V ), potassium (K V , K Ca ), chloride (Cl -) and nonselective ion channels (transient receptor potentials [TRPs]). VSICs have significant structural homology and common functional mechanisms. We outline the approaches and limitations and provide examples of targeting VSICs at the pores, voltage sensors and alternatively spliced sites. Rational drug design can come from an integrated view of the structure and mechanisms of gating and activation by voltage or mechanical stress.Keywords: functional GI, GI motility, ion channel, voltage gated ion channel, potassium voltage gated ion channel, sodium voltage gated ion channel, calcium voltage gated ion channel, chloride channelGastrointestinal functional and motility disorders Gastrointestinal (GI) functional and motility disorders are common and commonly morbid. In the broadest sense, GI functional and motility disorders refer to a group of disorders whose symptomatology is related to motor, sensory or even secretory function of the GI tract. The term 'functional' refers to the subgroup of disorders that do not yet have a well-defined pathophysiology. This broad definition means that the symptoms are nonspecific and include nausea, vomiting, bloating, abdominal discomfort or pain, constipation or diarrhea. Some of the most common motility disorders encountered in practice are achalasia, gastroparesis, intestinal pseudo-obstruction and slow transit constipation. Common functional GI disorders such as functional dyspepsia and irritable bowel syndrome (IBS) are highly prevalent in the community. For example, IBS has an estimated prevalence of 15-22% in Western society and by it...

Functional effects of β3-adrenoceptor on pacemaker activity in interstitial cells of Cajal from the mouse colon

“…The pacemaking mechanisms of small intestinal ICCs are coupled with IP 3 -dependent Ca 2 þ release from endoplasmic reticulum and the activation of pacemaker channels. Transient receptor potential (TRP) channels, Ca 2 þ -activated Cl À channels, are candidates for pacemaker potentials (Nakayama et al, 2007;Beyder and Farrugia, 2012;Zhu et al, 2009). Recently, we reported that hyperpolarization-activated cyclic nucleotide (HCN) channels are also involved in generating pacemaker potentials in colonic ICCs, and act as possible pacemaker channels (Shahi et al, 2014a).…”

Loss-of-Function of the Voltage-Gated Sodium Channel NaV1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome

“…Genotyping supports this notion, but specific impact of individual genes remains unclear. 5 Ion channels are excellent pathophysiologic and therapeutic targets because they are directly involved in both GI motility 6, 7 and visceral pain. 8 Therefore, ion channelopathies may cause IBS in some cases.…”

Altered globotriaosylceramide accumulation and mucosal neuronal fiber density in the colon of the Fabry disease mouse model

“…Functional GI disorders (FGIDs) are complex multisystem pathologies that involve abnormalities in GI secretion, motility, sensation, and central perception. Abdominal pain is a common and prominent feature of FGIDs . The role of ion channels in the transmission of visceral sensation is well established at mucosal, smooth muscular, and neuronal level .…”