Komuniecki R et al. (2012) Invert Neurosci "Monoamines activate neuropeptide signaling cascades to modulate nociception in C. elegans: a useful model for the modulation of chronic pain?"

Hapiak V, Komuniecki R, Wragg R, Bamber B, Harris G

[Invert Neurosci, 2012]

Monoamines and neuropeptides interact to modulate key behaviors in most organisms. This review is focused on the interaction between octopamine (OA) and an array of neuropeptides in the inhibition of a simple, sensory-mediated aversive behavior in the C. elegans model system and describes the role of monoamines in the activation of global peptidergic signaling cascades. OA has been often considered the invertebrate counterpart of norepinephrine, and the review also highlights the similarities between OA inhibition in C. elegans and the noradrenergic modulation of pain in higher organisms.

Zou WJ et al. (2012) Zhejiang Da Xue Xue Bao Yi Xue Ban "[Molecular mechanisms of TRP channels in mechano-sensory transduction]."

Kang LJ, Zou WJ, Huang GF

[Zhejiang Da Xue Xue Bao Yi Xue Ban, 2012]

Channels from the TRP superfamily have essential roles in a wide variety of sensory transductions, especially in mechano-sensation, such as hearing, touch and mechanical pain. TRP channels are also implicated in major channelopathies, including deafness, chronic pain, autosomal dominant polycystic kidney disease (ADPKD) and ventricular hypertrophy. As the leading candidates for mechano-sensitive channels, some TRP channels appear to be mechano-receptor, which can be activated by mechanical forces directly, such as C. elegans TRPN homolog TRP-4; whereas others may act as signal modulators, receiving and amplifying signals indirectly. This review is to introduce the function of TRPs in mechano-sensory transduction and to discuss the underlying molecular mechanisms.

Hamill OP et al. (1996) Trends in Neurosciences "A supramolecular complex underlying touch sensitivity."

Hamill OP, McBride DW

[Trends in Neurosciences, 1996]

Touch sensitivity in humans is dependent on highly specialized cutaneous nerve endings encapsulated in elaborate cellular structures such as the Pacinian, Ruffini and Meissner's corpuscles. Although the details of the encapsulations vary, the common theme involves the nerve endings making intimate mechanical linkages with the collagen-fiber networks contained within each capsule. Presumably, it is these external linkages with the membrane that serve to transmit and focus mechanical energy onto the mechanotransducers located in the nerve endings, and thus contribute to their low threshold and high mechanosensitivity. Extracellular mechanical linkages are also a feature of specific touch sensors in lower invertebrates, and thus appear to have evolved early in the animal kingdom. Indeed, it seems wherever high mechanosensitivity is required external mechanical linkages are present. In contrast, pain sensation, which is characterized by high threshold and low mechanosensitivity, is mediated by naked or free nerve endings, which lack elaborate external structures. Despite the existence of detailed ultrastructural information, the general inaccessibility of vertebrate touch and pain receptors has hampered studies on the molecules and molecular interactions underlying mechanotransduction in these cells. However, recent molecular-genetic analysis of touch-insensitive mutants in the tiny, free-swimming round worm, Caenorhabditis elegans, carried out by Martin Chalfie and colleagues, has begun to reveal detailed information on the molecular machinery of mechanotransduction. This information should provide useful clues and general principles for unravelling the molecular mechanisms underlying our own sensations of touch and pain.

Eastwood AL et al. (2012) Physiology (Bethesda) "Insight into DEG/ENaC channel gating from genetics and structure."

Goodman MB, Eastwood AL

[Physiology (Bethesda), 2012]

The founding members of the superfamily of DEG/ENaC ion channel proteins are C. elegans proteins that form mechanosensitive channels in touch and pain receptors. For more than a decade, the research community has used mutagenesis to identify motifs that regulate gating. This review integrates insight derived from unbiased in vivo mutagenesis screens with recent crystal structures to develop new models for activation of mechanically gated DEGs.

Bianchi L et al. (2002) Neuron "Protons at the gate: DEG/ENaC ion channels help us feel and remember."

Bianchi L, Driscoll M

[Neuron, 2002]

The DEG/ENaC ion channel family contributes to channels of striking functional diversity. Neuronally expressed family members include the C. elegans degenerins that mediate touch and are thought to be mechanically gated, and the mammalian ASICs, which are gated by protons. ASICs affect a range of sensory functions that includes perception of gentle touch, harsh touch, heat, sour taste, and pain. Family member ASIC1 is now implicated in long-term potentiation, suggesting that minute fluxes in synaptic pH may activate ASICs to enhance learning.

Tavernarakis N et al. (2001) Ann N Y Acad Sci "Degenerins. At the core of the metazoan mechanotransducer?"

Tavernarakis N, Driscoll M

[Ann N Y Acad Sci, 2001]

Mechanosensory signaling, believed to be mediated by mechanically gated ion channels, constitutes the basis for the senses of touch and hearing, and contributes fundamentally to the development and homeostasis of all organisms. Despite this profound importance in biology, little is known of the molecular identities or functional requirements of mechanically gated ion channels. Genetic analyses of touch sensation and locomotion in Caenorhabditis elegans have implicated a new class of ion channels, the degenerins (DEG) in nematode mechanotransduction. Related fly and vertebrate proteins, the epithelial sodium channel (ENaC) family, have been implicated in several important processes, including transduction of mechanical stimuli, pain sensation, gametogenesis, sodium reabsorption, and blood pressure regulation. Still-to-be-discovered DEG/ENaC proteins may compose the core of the elusive human mechanotransducer.

Harteneck C et al. (2000) Trends Neurosci "From worm to man: three subfamilies of TRP channels."

Harteneck C, Plant TD, Schultz G

[Trends Neurosci, 2000]

A steadily increasing number of cDNAs for proteins that are structurally related to the TRP ion channels have been cloned in recent years. All these proteins display a topology of six transmembrane segments that is shared with some voltage-gated channels and the cyclic-nucleotide-gated channels. The TRP channels can be divided, on the basis of their homology, into three TRP channel (TRPC) subfamilies: short (S), long (L) and osm (O). From the evidence available to date, this subdivision can also be made according to channel function. Thus, the STRPC family, which includes Drosophila TRP and TRPL and the mammalian homologues, TRPC1-7, is a family of Ca2+-permeable cation channels that are activated subsequent to receptor-mediated stimulation of different isoforms of phospholipase C. Members of the OTRPC family are Ca2+-permeable channels involved in pain transduction (vanilloid and vanilloid-like receptors), epithelial Ca2+ transport and, at least in Caenorhabditis elegans, in chemo-, mechano- and osmoregulation. The LTRPC family is less well characterized.

Mano I et al. (1999) Bioessays "DEG/ENaC channels: a touchy superfamily that watches its salt."

Mano I, Driscoll MA

[Bioessays, 1999]

To the surprise of many, studies of molecular mechanisms of touch transduction and analyses of epithelial Na+ transport have converged to define a new class of ion channel subunits. Based on the names of the first two identified subfamilies, the Caenorhabditis elegans degenerins and the vertebrate epithelial amiloride-sensitive Na+ channel, this ion channel class is called the DEG/ENaC superfamily. Members of the DEG/ENaC superfamily have been found in nematodes, flies, snails, and vertebrates. Family members share common topology, such that they span the membrane twice and have intracellular N- and C-termini; a large extracellular loop includes a conserved cysteine-rich region. DEG/ENaC channels have been implicated a broad spectrum of cellular functions, including mechanosensation, proprioception, pain sensation, gametogenesis, and epithelial Na+ transport. These channels exhibit diverse gating properties, ranging from near constitutive opening to rapid inactivation. We discuss working understanding of DEG/ENaC functions, channel properties, structure/activity correlations and possible evolutionary relationship to other channel classes.

Kellenberger S et al. (2002) Physiol Rev "Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure."

Schild L, Kellenberger S

[Physiol Rev, 2002]

The recently discovered epithelial sodium channel (ENaC)/degenerin (DEG) gene family encodes sodium channels involved in various cell functions in metazoans. Subfamilies found in invertebrates or mammals are functionally distinct. The degenerins in Caenorhabditis elegans participate in mechanotransduction in neuronal cells, FaNaC in snails is a ligand-gated channel activated by neuropeptides, and the Drosophila subfamily is expressed in gonads and neurons. In mammals, ENaC mediates Na(+) transport in epithelia and is essential for sodium homeostasis. The ASIC genes encode proton-gated cation channels in both the central and peripheral nervous system that could be involved in pain transduction. This review summarizes the physiological roles of the different channels belonging to this family, their biophysical and pharmacological characteristics, and the emerging knowledge of their molecular structure. Although functionally different, the ENaC/DEG family members share functional domains that are involved in the control of channel activity and in the formation of the pore. The functional heterogeneity among the members of the ENaC/DEG channel family provides a unique opportunity to address the molecular basis of basic channel functions such as activation by ligands, mechanotransduction, ionic selectivity, or block by pharmacological ligands.

Yang NJ et al. (2017) J Mol Biol "Bacterial Signaling to the Nervous System through Toxins and Metabolites."

Yang NJ, Chiu IM

[J Mol Biol, 2017]

Mammalian hosts interface intimately with commensal and pathogenic bacteria. It is increasingly clear that molecular interactions between the nervous system and microbes contribute to health and disease. Both commensal and pathogenic bacteria are capable of producing molecules that act on neurons and affect essential aspects of host physiology. Here we highlight several classes of physiologically important molecular interactions that occur between bacteria and the nervous system. First, clostridial neurotoxins block neurotransmission to or from neurons by targeting the SNARE complex, causing the characteristic paralyses of botulism and tetanus during bacterial infection. Second, peripheral sensory neurons-olfactory chemosensory neurons and nociceptor sensory neurons-detect bacterial toxins, formyl peptides, and lipopolysaccharides through distinct molecular mechanisms to elicit smell and pain. Bacteria also damage the central nervous system through toxins that target the brain during infection. Finally, the gut microbiota produces molecules that act on enteric neurons to influence gastrointestinal motility, and metabolites that stimulate the "gut-brain axis" to alter neural circuits, autonomic function, and higher-order brain function and behavior. Furthering the mechanistic and molecular understanding of how bacteria affect the nervous system may uncover potential strategies for modulating neural function and treating neurological diseases.