Role Of Sensory Signals Research Articles

An overview on transient receptor potential channels superfamily.

The transient receptor potential (TRP) channel superfamily is comprised of a large group of cation-permeable channels, which display an extraordinary diversity of roles in sensory signaling and are involved in plethora of animal behaviors. These channels are activated through a wide variety of mechanisms and participate in virtually every sensory modality. Modulating TRP channel activity provides an important way to regulate membrane excitability and intracellular calcium levels. This is reflected by the fact that small molecule compounds modulating different TRPs have all entered clinical trials for a variety of diseases. The role of TRPs will be further elucidated in complex diseases of the nervous, intestinal, renal, urogenital, respiratory, and cardiovascular systems in diverse therapeutic areas including pain and itch, headache, pulmonary function, oncology, neurology, visceral organs, and genetic diseases. This review focuses on recent developments in the TRP ion channel-related area and highlights evidence supporting TRP channels as promising targets for new analgesic drugs for therapeutic intervention. This review presents a variety of: (1) phylogeny aspects of TRP channels; (2) some structural and functional characteristics of TRPs; (3) a general view and short characteristics of main seven subfamilies of TRP channels; (4) the evidence for consider TRP channels as therapeutic and analgesic targets; and finally (5) further perspectives of TRP channels research.

A Presynaptic Group III mGluR Recruits Gβγ/SNARE Interactions to Inhibit Synaptic Transmission by Cone Photoreceptors in the Vertebrate Retina.

G-protein βγ subunits (Gβγ) interact with presynaptic proteins and regulate neurotransmitter release downstream of Ca2+ influx. To accomplish their roles in sensory signaling, photoreceptor synapses use specialized presynaptic proteins that support neurotransmission at active zone structures known as ribbons. While several G-protein coupled receptors (GPCRs) influence synaptic transmission at ribbon synapses of cones and other retinal neurons, it is unknown whether Gβγ contributes to these effects. We tested whether activation of one particular GPCR, a metabotropic glutamate receptor (mGluR), can reduce cone synaptic transmission via Gβγ in tiger salamander retinas. In recordings from horizontal cells, we found that an mGluR agonist (L-AP4) reduced cone-driven light responses and mEPSC frequency. In paired recordings of cones and horizontal cells, L-AP4 slightly reduced cone ICa (∼10%) and caused a larger reduction in cone-driven EPSCs (∼30%). Proximity ligation assay revealed direct interactions between SNAP-25 and Gβγ subunits in retinal synaptic layers. Pretreatment with the SNAP-25 cleaving protease BoNT/A inhibited L-AP4 effects on synaptic transmission, as did introduction of a peptide derived from the SNAP-25 C terminus. Introducing Gβγ subunits directly into cones reduced EPSC amplitude. This effect was inhibited by BoNT/A, supporting a role for Gβγ/SNAP-25 interactions. However, the mGluR-dependent reduction in ICa was not mimicked by Gβγ, indicating that this effect was independent of Gβγ. The finding that synaptic transmission at cone ribbon synapses is regulated by Gβγ/SNAP-25 interactions indicates that these mechanisms are shared by conventional and ribbon-type synapses. Gβγ liberated from other photoreceptor GPCRs is also likely to regulate synaptic transmission.SIGNIFICANCE STATEMENT Dynamic regulation of synaptic transmission by presynaptic G-protein coupled receptors shapes information flow through neural circuits. At the first synapse in the visual system, presynaptic metabotropic glutamate receptors (mGluRs) regulate cone photoreceptor synaptic transmission, although the mechanisms and functional impact of this are unclear. We show that mGluRs regulate light response encoding across the cone synapse, accomplished in part by triggering G-protein βγ subunits (Gβγ) interactions with SNAP-25, a core component of the synaptic vesicle fusion machinery. In addition to revealing a role in visual processing, this provides the first demonstration that Gβγ/SNAP-25 interactions regulate synaptic function at a ribbon-type synapse, contributing to an emerging picture of the ubiquity of Gβγ/SNARE interactions in regulating synaptic transmission throughout the nervous system.

The role of sensory signals in perception of the body

The role of sensory signals in perception of the body

Expression Level Dependence of the Gating and Permeation Properties of P2X Receptor Channels

P2X receptors are cation channels that are activated by extracellular ATP, and that are widely expressed in virtually every tissue. Seven subtypes of P2X receptors have been identified in mammals, and they play important roles in sensory signaling and inflammation. The expression levels of P2X receptors have been reported to change in response to various stimuli. For instance, the expression level of P2X4 receptors increased strikingly in microglia of spinal cord after nerve injury, and these receptors were suggested to play important roles for tactile allodynia1. Interestingly, it has also been reported that both gating and permeation properties of some P2X receptors change in a channel-density dependent manner2,3. Here we transfected P2X2 receptor channels into HEK293 cells with either high or low expression vectors, and then studied the properties of these channels at varying expression levels. Our results suggest that the selectivity, rectification and ATP sensitivity of P2X receptor channels exhibit expression level dependence, as if distinct open states predominate at different expression levels. These changes do not appear to result from artefactual changes in intracellular ion concentrations or voltage errors, and we are currently studying the underlying mechanism.

Controlled Activation of Heteromeric P2X Receptors by ATP and Magnesium

P2X receptor channels are a family of trimeric cation channels that are activated by extracelluar ATP. Seven subtypes of P2X receptors have been identified in mammals, and they are widely distributed throughout the body, serving important roles in sensory signaling and inflammation. In physiological solutions, ATP is ionized and primarily found in complex with Mg2+. We recently found (Li, Silberberg and Swartz, 2013 PNAS 110, E3455-63) that the slowly desensitizing P2X2 and P2X4 receptors can be activated by free ATP, but MgATP2- promotes opening with very low efficacy; Mg2+ thus acts as a competitive antagonist. In contrast, both free ATP and MgATP2− robustly open the rapidly desensitizing P2X3 subtype, although P2X3 receptor channel currents are inhibited by Mg2+ through an allosteric mechanism. Interestingly, both inhibitory effects of Mg2+ are disengaged in heteromeric P2X2/3 channels. In the present study we investigated the properties that P2X6 when forming heteromeric channels with P2X2 and P2X4 subunits. The P2X6 subunit is abundantly expressed in the central nervous system along with P2X2 and P2X4, yet does not form functional homomeric channels on its own. When co-expressed in HEK cells, we find that heteromeric P2X2/6 and P2X4/6 channels are functional, and unlike homomeric P2X2 and P2X4 receptors, can be efficiently activated by MgATP2-. Our results also suggest that Mg2+ allosterically regulates P2X2/6 heteromeric channels and we are currently investigating the underlying mechanism and site of activation. Taken together, our results support the general idea that heteromulterimerization of P2X receptor channels influences the forms of ATP that can activate these channels and the regulatory influences of Mg2+.

Evolutionarily conserved, multitasking TRP channels: lessons from worms and flies.

The Transient Receptor Potential (TRP) channel family is comprised of a large group of cation-permeable channels, which display an extraordinary diversity of roles in sensory signaling. TRPs allow animals to detect chemicals, mechanical force, light, and changes in temperature. Consequently, these channels control a plethora of animal behaviors. Moreover, their functions are not limited to the classical senses, as they are cellular sensors, which are critical for ionic homeostasis and metabolism. Two genetically tractable invertebrate model organisms, Caenorhabditis elegans and Drosophila melanogaster, have led the way in revealing a wide array of sensory roles and behaviors that depend on TRP channels. Two overriding themes have emerged from these studies. First, TRPs are multitasking proteins, and second, many functions and modes of activation of these channels are evolutionarily conserved, including some that were formerly thought to be unique to invertebrates, such as phototransduction. Thus, worms and flies offer the potential to decipher roles for mammalian TRPs, which would otherwise not be suspected.

Subtype-Specific Control of P2X Receptor Signaling by ATP and Magnesium

The identity and forms of activating ligands for ion channels are fundamental to their physiological roles in rapid electrical signaling. P2X receptor channels are ATP-activated cation channels that serve important roles in sensory signaling and inflammation, yet the active forms of the nucleotide are unknown. In physiological solutions, ATP is ionized and primarily found in complex with Mg2+. In this study we investigated the active forms of ATP and find that the action of MgATP2- and ATP4- differ between subtypes of P2X receptors. The slowly desensitizing P2X2 receptor can be activated by free ATP, but MgATP2- promotes opening with very low efficacy. In contrast, both free ATP and MgATP2- robustly open the rapidly desensitizing P2X3 subtype. A further distinction between these two subtypes is the ability of Mg2+ to regulate P2X3 through a distinct allosteric mechanism. Importantly, heteromeric P2X2/3 channels present in sensory neurons exhibit a hybrid phenotype, characterized by robust activation by MgATP2- and weak regulation by Mg2+. These results reveal the existence of two classes of homomeric P2X receptors with differential sensitivity to MgATP2- and regulation by Mg2+, and demonstrate that both restraining mechanisms can be disengaged in heteromeric P2X2/3 receptor channels. We are currently investigating if our findings with P2X2/3 receptor channels can be generalized to other subtypes of homomeric and heteromeric P2X receptors.