Ca2+ is a highly versatile intracellular signal that operates over a wide temporal range to regulate many different cellular processes. An extensive Ca2+-signalling toolkit is used to assemble signalling systems with very different spatial and temporal dynamics. Rapid highly localized Ca2+ spikes regulate fast responses, whereas slower responses are controlled by repetitive global Ca2+ transients or intracellular Ca2+ waves. Ca2+ has a direct role in controlling the expression patterns of its signalling systems that are constantly being remodelled in both health and disease.

/pdf/calcium-signalling-dynamics-homeostasis-and-remodelling-2oni038yeg.pdf

Calcium signalling: dynamics, homeostasis and remodelling

TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.

TRP channels as cellular sensors

In electrically nonexcitable cells, Ca2+ influx is essential for regulating a host of kinetically distinct processes involving exocytosis, enzyme control, gene regulation, cell growth and prolifera...

Store-operated calcium channels.

The Na+/Ca2+ exchanger, an ion transport protein, is expressed in the plasma membrane (PM) of virtually all animal cells. It extrudes Ca2+ in parallel with the PM ATP-driven Ca2+ pump. As a reversible transporter, it also mediates Ca2+ entry in parallel with various ion channels. The energy for net Ca2+ transport by the Na+/Ca2+ exchanger and its direction depend on the Na+, Ca2+, and K+ gradients across the PM, the membrane potential, and the transport stoichiometry. In most cells, three Na+ are exchanged for one Ca2+. In vertebrate photoreceptors, some neurons, and certain other cells, K+ is transported in the same direction as Ca2+, with a coupling ratio of four Na+ to one Ca2+ plus one K+. The exchanger kinetics are affected by nontransported Ca2+, Na+, protons, ATP, and diverse other modulators. Five genes that code for the exchangers have been identified in mammals: three in the Na+/Ca2+ exchanger family (NCX1, NCX2, and NCX3) and two in the Na+/Ca2+ plus K+ family (NCKX1 and NCKX2). Genes homologous to NCX1 have been identified in frog, squid, lobster, and Drosophila. In mammals, alternatively spliced variants of NCX1 have been identified; dominant expression of these variants is cell type specific, which suggests that the variations are involved in targeting and/or functional differences. In cardiac myocytes, and probably other cell types, the exchanger serves a housekeeping role by maintaining a low intracellular Ca2+ concentration; its possible role in cardiac excitation-contraction coupling is controversial. Cellular increases in Na+ concentration lead to increases in Ca2+ concentration mediated by the Na+/Ca2+ exchanger; this is important in the therapeutic action of cardiotonic steroids like digitalis. Similarly, alterations of Na+ and Ca2+ apparently modulate basolateral K+ conductance in some epithelia, signaling in some special sense organs (e.g., photoreceptors and olfactory receptors) and Ca2+-dependent secretion in neurons and in many secretory cells. The juxtaposition of PM and sarco(endo)plasmic reticulum membranes may permit the PM Na+/Ca2+ exchanger to regulate sarco(endo)plasmic reticulum Ca2+ stores and influence cellular Ca2+ signaling.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.3.763

Sodium/Calcium Exchange: Its Physiological Implications

The aim of this review is to provide a basic framework for understanding the function of mammalian transient receptor potential (TRP) channels, particularly as they have been elucidated in heterologous expression systems. Mammalian TRP channel proteins form six-transmembrane (6-TM) cation-permeable channels that may be grouped into six subfamilies on the basis of amino acid sequence homology (TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML). Selected functional properties of TRP channels from each subfamily are summarized in this review. Although a single defining characteristic of TRP channel function has not yet emerged, TRP channels may be generally described as calcium-permeable cation channels with polymodal activation properties. By integrating multiple concomitant stimuli and coupling their activity to downstream cellular signal amplification via calcium permeation and membrane depolarization, TRP channels appear well adapted to function in cellular sensation. Our review of recent literature implicating TRP channels in neuronal growth cone steering suggests that TRPs may function more widely in cellular guidance and chemotaxis. The TRP channel gene family and its nomenclature, the encoded proteins and alternatively spliced variants, and the rapidly expanding pharmacology of TRP channels are summarized in online supplemental material.

An Introduction to TRP Channels

http://blog.ub.ac.id/fawzy/files/2013/09/Coding-of-Sweet-Bitter-and-Umami-Tastes.pdf

Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways.

TRP channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. This family was designated TRP because of a spontaneously occurring Drosoph...

https://www.physiology.org/doi/pdf/10.1152/physrev.00001.2002

TRP Channel Proteins and Signal Transduction

The Drosophila Piezo protein is shown to function in sensory neurons to transduce mechanical force in vivo. Many tissues are able to detect and respond to mechanical forces, and this mechanical sensitivity has been implicated in many biological processes and diseases, including touch, pain, deafness and hypertension. The conversion of mechanical force into biological signals, or 'mechanotransduction', is thought to involve specialized cation channels. In a pair of papers, Ardem Patapoutian and colleagues establish that the large transmembrane proteins of the 'Piezo' family — conserved from animals to plants and protozoa — are among the long-sought-after mechanically activated ion channels. Coste et al. show that the Drosophila melanogaster Piezo protein induces mechanically activated cationic currents in human embryonic kidney cells, establishing functional conservation. Comparison of the mechanically activated currents induced by mouse and fly Piezos reveals ion-channel activities with unique pore properties, suggesting that Piezos are bona fide ion channels. Kim et al. show that D. melanogaster Piezo is essential for sensing mechanical pain in fruitflies, giving the first demonstration that Piezos are physiologically relevant mechanosensors in vivo. Transduction of mechanical stimuli by receptor cells is essential for senses such as hearing, touch and pain1,2,3,4. Ion channels have a role in neuronal mechanotransduction in invertebrates1; however, functional conservation of these ion channels in mammalian mechanotransduction is not observed. For example, no mechanoreceptor potential C (NOMPC), a member of transient receptor potential (TRP) ion channel family, acts as a mechanotransducer in Drosophila melanogaster5 and Caenorhabditis elegans6,7; however, it has no orthologues in mammals. Degenerin/epithelial sodium channel (DEG/ENaC) family members are mechanotransducers in C. elegans8 and potentially in D. melanogaster9; however, a direct role of its mammalian homologues in sensing mechanical force has not been shown. Recently, Piezo1 (also known as Fam38a) and Piezo2 (also known as Fam38b) were identified as components of mechanically activated channels in mammals10. The Piezo family are evolutionarily conserved transmembrane proteins. It is unknown whether they function in mechanical sensing in vivo and, if they do, which mechanosensory modalities they mediate. Here we study the physiological role of the single Piezo member in D. melanogaster (Dmpiezo; also known as CG8486). Dmpiezo expression in human cells induces mechanically activated currents, similar to its mammalian counterparts11. Behavioural responses to noxious mechanical stimuli were severely reduced in Dmpiezo knockout larvae, whereas responses to another noxious stimulus or touch were not affected. Knocking down Dmpiezo in sensory neurons that mediate nociception and express the DEG/ENaC ion channel pickpocket (ppk) was sufficient to impair responses to noxious mechanical stimuli. Furthermore, expression of Dmpiezo in these same neurons rescued the phenotype of the constitutive Dmpiezo knockout larvae. Accordingly, electrophysiological recordings from ppk-positive neurons revealed a Dmpiezo-dependent, mechanically activated current. Finally, we found that Dmpiezo and ppk function in parallel pathways in ppk-positive cells, and that mechanical nociception is abolished in the absence of both channels. These data demonstrate the physiological relevance of the Piezo family in mechanotransduction in vivo, supporting a role of Piezo proteins in mechanosensory nociception.

The role of Drosophila Piezo in mechanical nociception

In Drosophila photoreceptors, phospholipase C (PLC) and other signalling components form multiprotein structures through the PDZ scaffold protein INAD. Association between PLC and INAD is important for termination of responses to light; the underlying mechanism is, however, unclear. Here we report that the maintenance of large amounts of PLC in the signalling membranes by association with INAD facilitates response termination, and show that PLC functions as a GTPase-activating protein (GAP). The inactivation of the G protein by its target, the PLC, is crucial for reliable production of single-photon responses and for the high temporal and intensity resolution of the response to light.

Phospholipase C and termination of G-protein-mediated signalling in vivo.

Capacitative Ca2+ entry is a component of the inositol-lipid signaling in which depletion of inositol 1,4,5-trisphosphate (InsP3)-sensitive Ca2+ stores activates Ca2+ influx by a mechanism that is still unknown. This pathway plays a central role in cellular signaling, which is mediated by many hormones, neurotransmitters, and growth factors. Studies of Drosophila photoreceptors provided the first putative capacitative Ca2+ entry mutant designated transient receptor potential (trp) and a Drosophila gene encoding TRP-like protein (trpl). It is not clear how the Ca2+ store depletion signal is relayed to the plasma membrane and whether both TRP and TRPL participate in this process. We report here that coexpressing Drosophila TRP and TRPL in Xenopus oocytes synergistically enhances the endogenous Ca2+-activated Cl− current and produces a divalent inward current. Both of these currents are activated by Ca2+ store depletion. In the absence of Ca2+, Mg2+ is the main charge carrier of the divalent current. This current is characterized by lanthanum sensitivity and a voltage-dependent blocking effect of Mg2+, which is relieved at both hyperpolarizing (inward rectification) and depolarizing (outward rectification) potentials. The store-operated divalent current is neither observed in native oocytes nor in oocytes expressing either TRP or TRPL alone. The production of this current implicates a cooperative action of TRP and TRPL in the depletion-activated current.

https://www.pnas.org/content/pnas/93/24/14146.full.pdf

Boaz Cook

Papers

Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways.

TRP Channel Proteins and Signal Transduction

The role of Drosophila Piezo in mechanical nociception

Phospholipase C and termination of G-protein-mediated signalling in vivo.

Coexpression of Drosophila TRP and TRP-like proteins in Xenopus oocytes reconstitutes capacitative Ca2+ entry