ENaCs and ASICs as therapeutic targets

Abstract

<jats:p>The epithelial Na<jats:sup>+</jats:sup>channel (ENaC) and acid-sensitive ion channel (ASIC) branches of the ENaC/degenerin superfamily of cation channels have drawn increasing attention as potential therapeutic targets in a variety of diseases and conditions. Originally thought to be solely expressed in fluid absorptive epithelia and in neurons, it has become apparent that members of this family exhibit nearly ubiquitous expression. Therapeutic opportunities range from hypertension, due to the role of ENaC in maintaining whole body salt and water homeostasis, to anxiety disorders and pain associated with ASIC activity. As a physiologist intrigued by the fundamental mechanics of salt and water transport, it was natural that Dale Benos, to whom this series of reviews is dedicated, should have been at the forefront of research into the amiloride-sensitive sodium channel. The cloning of ENaC and subsequently the ASIC channels has revealed a far wider role for this channel family than was previously imagined. In this review, we will discuss the known and potential roles of ENaC and ASIC subunits in the wide variety of pathologies in which these channels have been implicated. Some of these, such as the role of ENaC in Liddle's syndrome are well established, others less so; however, all are related in that the fundamental defect is due to inappropriate channel activity.</jats:p>

Gating Transitions in the Palm Domain of ASIC1a*

“…ASICs have been proposed as potential therapeutic targets to treat pain, psychiatric disorders, and neurodegenerative diseases (8,28). Yu et al (29) identified 2-guanidine-4-methylquinazoline (GMQ) as a non-proton ligand for ASIC3.…”

Hyperactivation of the Mammalian Degenerin MDEG Promotes Caspase-8 Activation and Apoptosis

“…The degenerin/epithelial sodium channels (DEG/ENaC) 2 are a family of amiloride-sensitive cell surface channels that allow apical entry of cations including Na ϩ and Li ϩ into cells. Some of these channels are nonselective and are permeable to larger ions such as K ϩ and Ca 2ϩ .…”

“…Proper function of these channels is critical for maintaining cellular ion homeostasis and osmotic balance. Although previously thought to be mostly expressed in fluid absorptive epithelia and in neurons, these channels have since been found to be expressed in most tissues (1,2). Dysregulation of DEG/ENaC channels has been implicated in numerous pathological conditions ranging from hypertension, anxiety disorder, and neurodegenerative disorder to cancer, many of which are associated with hyperactivation-induced cytotoxicity.…”

“…Dysregulation of DEG/ENaC channels has been implicated in numerous pathological conditions ranging from hypertension, anxiety disorder, and neurodegenerative disorder to cancer, many of which are associated with hyperactivation-induced cytotoxicity. Modulation of DEG/ENaC channel activity has become an emerging therapeutic opportunity (2)(3)(4).…”

Acid Sensing Ion Channels (Asics): Potential Targets for the Discovery of Novel Therapeutics in Disease Management

“…A s rong ASIC-media ed depolarization, however, can inhibi an already actively signaling neuron. ASIC1a has a small permeabili y for Ca2+ in addition o i s Na+ permeabili y, and some of i s cellular functions, as for example neurodegeneration after ischem-ic s roke are hough o depend on a Ca2+ en ry in o he cell [31][32][33][34][35][36]. Expression pattern of ASIC subuni s in differen cells and tissue ypes of functional organization are represen ed in Table 1.…”