Johnson CA et al. (2022) Biomolecules "Unconventional Myosins from Caenorhabditis elegans as a Probe to Study Human Orthologues."

Johnson CA, Buss F, Behbehani R

[Biomolecules, 2022]

Unconventional myosins are a superfamily of actin-based motor proteins that perform a number of roles in fundamental cellular processes, including (but not limited to) intracellular trafficking, cell motility, endocytosis, exocytosis and cytokinesis. 40 myosins genes have been identified in humans, which belong to different 12 classes based on their domain structure and organisation. These genes are widely expressed in different tissues, and mutations leading to loss of function are associated with a wide variety of pathologies while over-expression often results in cancer. Caenorhabditis elegans (C. elegans) is a small, free-living, non-parasitic nematode. ~38% of the genome of C. elegans has predicted orthologues in the human genome, making it a valuable tool to study the function of human counterparts and human diseases. To date, 8 unconventional myosin genes have been identified in the nematode, from 6 different classes with high homology to human paralogues. The hum-1 and hum-5 (heavy chain of an unconventional myosin) genes encode myosin of class I, hum-2 of class V, hum-3 and hum-8 of class VI, hum-6 of class VII and hum-7 of class IX. The hum-4 gene encodes a high molecular mass myosin (307 kDa) that is one of the most highly divergent myosins and is a member of class XII. Mutations in many of the human orthologues are lethal, indicating their essential properties. However, a functional characterisation for many of these genes in C. elegans has not yet been performed. This article reviews the current knowledge of unconventional myosin genes in C. elegans and explores the potential use of the nematode to study the function and regulation of myosin motors to provide valuable insights into their role in diseases.

Wheatly MG (1999) J Exp Zool "Calcium homeostasis in crustacea: the evolving role of branchial, renal, digestive and hypodermal epithelia."

Wheatly MG

[J Exp Zool, 1999]

Crustaceans serve as an ideal model for the study of calcium homeostasis due to their natural molting cycle. Demineralization and remineralization of the calcified cuticle is accompanied by bidirectional Ca transfer across the primary Ca transporting epithelia: gills, antennal gland (kidney), digestive system, and cuticular hypodermis. The review will demonstrate how a continuum of crustaceans can be used as a paradigm for the evolution of Ca transport mechanisms. Generally speaking, aquatic crustaceans rely primarily on branchial Ca uptake and accordingly are affected by water Ca content; terrestrial crustaceans rely on intake of dietary Ca across the digestive epithelium. Synchrony of mineralization at the cuticle vs. storage sites will be presented Physiological and behavioral adaptations have evolved to optimize Ca balance during the molting cycle in different Ca environments. Intracellular Ca regulation reveals common mechanisms of apical and basolateral membrane transport as well as intracellular sequestration. Regulation of cell Ca concentration will be discussed in intermolt and during periods of the molting cycle when transepithelial Ca flux is significantly elevated. Molecular characterization of the sarco-/endoplasmic reticular Ca pump in aquatic species reveals the presence of two isoforms that originate from a single gene. This gene is differentially expressed during the molting cycle. Gene expression may be regulated by a suite of hormones including ecdysone, calcitonin, and vitamin D. Perspectives for future research are presented.

Burgoyne RD et al. (2015) Biochim Biophys Acta "Sense and specificity in neuronal calcium signalling."

Haynes LP, Burgoyne RD

[Biochim Biophys Acta, 2015]

Changes in the intracellular free calcium concentration ([Ca]i) in neurons regulate many and varied aspects of neuronal function over time scales from microseconds to days. The mystery is how a single signalling ion can lead to such diverse and specific changes in cell function. This is partly due to aspects of the Ca signal itself, including its magnitude, duration, localisation and persistent or oscillatory nature. The transduction of the Ca signal requires Cabinding to various Ca sensor proteins. The different properties of these sensors are important for differential signal processing and determine the physiological specificity of Ca(2+) signalling pathways. A major factor underlying the specific roles of particular Ca sensor proteins is the nature of their interaction with target proteins and how this mediates unique patterns of regulation. We review here recent progress from structural analyses and from functional analyses in model organisms that have begun to reveal the rules that underlie Ca sensor protein specificity for target interaction. We discuss three case studies exemplifying different aspects of Ca sensor/target interaction. This article is part of a special issue titled the 13th European Symposium on Calcium.

Strange K et al. (2007) Cell Calcium "Physiological roles of STIM1 and Orai1 homologs and CRAC channels in the genetic model organism Caenorhabditis elegans."

Xing J, Yan X, Strange K, Lorin-Nebel C

[Cell Calcium, 2007]

The nematode Caenorhabditis elegans provides numerous experimental advantages for developing an integrative molecular understanding of physiological processes and has proven to be a valuable model for characterizing Ca(2+) signaling mechanisms. This review will focus on the role of Ca(2+) release activated Ca(2+) (CRAC) channel activity in function of the worm gonad and intestine. Inositol 1,4,5-trisphosphate (IP(3))-dependent oscillatory Ca(2+) signaling regulates contractile activity of the gonad and rhythmic posterior body wall muscle contraction (pBoc) required for ovulation and defecation, respectively. The C. elegans genome contains a single homolog of both STIM1 and Orai1, proteins required for CRAC channel function in mammalian and Drosophila cells. C. elegans STIM-1 and ORAI-1 are coexpressed in the worm gonad and intestine and give rise to robust CRAC channel activity when coexpressed in HEK293 cells. STIM-1 or ORAI-1 knockdown causes complete sterility demonstrating that the genes are essential components of gonad Ca(2+) signaling. Knockdown of either protein dramatically inhibits intestinal cell CRAC channel activity, but surprisingly has no effect on pBoc, intestinal Ca(2+) oscillations or intestinal ER Ca(2+) store homeostasis. CRAC channels thus do not play obligate roles in all IP(3)-dependent signaling processes in C. elegans. Instead, we suggest that CRAC channels carry out highly specialized and cell specific signaling roles and that they may function as a failsafe mechanism to prevent Ca(2+) store depletion under pathophysiological and stress conditions.

Ma Z et al. (2015) Pflugers Arch "Calcium homeostasis modulator (CALHM) ion channels."

Ma Z, Tanis JE, Foskett JK, Taruno A

[Pflugers Arch, 2015]

Calcium homeostasis modulator 1 (CALHM1), formerly known as FAM26C, was recently identified as a physiologically important plasma membrane ion channel. CALHM1 and its Caenorhabditis elegans homolog, CLHM-1, are regulated by membrane voltage and extracellular Ca(2+) concentration ([Ca(2+)]o). In the presence of physiological [Ca(2+)]o (1.5mM), CALHM1 and CLHM-1 are closed at resting membrane potentials but can be opened by strong depolarizations. Reducing [Ca(2+)]o increases channel open probability, enabling channel activation at negative membrane potentials. Together, voltage and Ca(2+) o allosterically regulate CALHM channel gating. Through convergent evolution, CALHM has structural features that are reminiscent of connexins and pannexins/innexins/LRRC8 (volume-regulated anion channel (VRAC)) gene families, including four transmembrane helices with cytoplasmic amino and carboxyl termini. A CALHM1 channel is a hexamer of CALHM1 monomers with a functional pore diameter of 14A. CALHM channels discriminate poorly among cations and anions, with signaling molecules including Ca(2+) and ATP able to permeate through its pore. CALHM1 is expressed in the brain where it plays an important role in cortical neuron excitability induced by low [Ca(2+)]o and in type II taste bud cells in the tongue that sense sweet, bitter, and umami tastes where it functions as an essential ATP release channel to mediate nonsynaptic neurotransmitter release. CLHM-1 is expressed in C. elegans sensory neurons and body wall muscles, and its genetic deletion causes locomotion defects. Thus, CALHM is a voltage- and Ca(2+) o-gated ion channel, permeable to large cations and anions, that plays important roles in physiology.

Singaravelu G et al. (2013) Cell Calcium "Calcium signaling surrounding fertilization in the nematode Caenorhabditis elegans."

Singaravelu G, Singson A

[Cell Calcium, 2013]

Calcium plays a prominent role during fertilization in many animals. This review focuses on roles of Ca(2+) during the events around fertilization in the model organism, Caenorhabditis elegans. Specifically, the role of Ca(2+) in sperm, oocytes and the surrounding somatic tissues during fertilization will be discussed, with the focus on sperm activation, meiotic maturation of oocytes, ovulation, sperm-egg interaction and fertilization.

Johnstone LS et al. (2010) J Cell Mol Med "STIM proteins: integrators of signalling pathways in development, differentiation and disease."

Dziadek MA, Johnstone LS, Graham SJ

[J Cell Mol Med, 2010]

The stromal interaction molecules STIM1 and STIM2 are endoplasmic reticulum Ca(2+) sensors, serving to detect changes in receptor-mediated ER Ca(2+) store depletion and to relay this information to plasma membrane localized proteins, including the store-operated Ca(2+) channels of the ORAI family. The resulting Ca(2+) influx sustains the high cytosolic Ca(2+) levels required for activation of many intracellular signal transducers such as the NFAT family of transcription factors. Models of STIM protein deficiency in mice, Drosophila melanogaster and Caenorhabditis elegans, in addition to the phenotype of patients bearing mutations in STIM1 have provided great insight into the role of these proteins in cell physiology and pathology. It is now becoming clear that STIM1 and STIM2 are critical for the development and functioning of many cell types, including lymphocytes, skeletal and smooth muscle myoblasts, adipocytes and neurons, and can interact with a variety of signalling proteins and pathways in a cell- and tissue-type specific manner. This review focuses on the role of STIM proteins in development, differentiation and disease, in particular highlighting the functional differences between STIM1 and STIM2.

Alvarez J et al. (2020) Cells "The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models."

Fonteriz RI, Garcia-Casas P, Montero M, Alvarez-Illera P, Alvarez J

[Cells, 2020]

Ca²⁺ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca²⁺ signaling is one of the key events in the development of neurodegenerative processes, an idea called the &quot;calcium hypothesis&quot; of neurodegeneration. <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) is a very good model for the study of aging and neurodegeneration. In fact, many of the signaling pathways involved in longevity were first discovered in this nematode, and many models of neurodegenerative diseases have also been developed therein, either through mutations in the worm genome or by expressing human proteins involved in neurodegeneration (-amyloid, -synuclein, polyglutamine, or others) in defined worm tissues. The worm is completely transparent throughout its whole life, which makes it possible to carry out Ca²⁺ dynamics studies in vivo at any time, by expressing Ca²⁺ fluorescent probes in defined worm tissues, and even in specific organelles such as mitochondria. This review will summarize the evidence obtained using this model organism to understand the role of Ca²⁺ signaling in aging and neurodegeneration.

Cohen SM et al. (2015) Biochem Biophys Res Commun "Evolutionary and functional perspectives on signaling from neuronal surface to nucleus."

Tsien RW, Ma H, Cohen SM, Li B

[Biochem Biophys Res Commun, 2015]

Reliance on Ca(2+) signaling has been well-preserved through the course of evolution. While the complexity of Ca(2+) signaling pathways has increased, activation of transcription factors including CREB by Ca(2+)/CaM-dependent kinases (CaMKs) has remained critical for long-term plasticity. In C. elegans, the CaMK family is made up of only three members, and CREB phosphorylation is mediated by CMK-1, the homologue of CaMKI. CMK-1 nuclear translocation directly regulates adaptation of thermotaxis behavior in response to changes in the environment. In mammals, the CaMK family has been expanded from three to ten members, enabling specialization of individual elements of a signal transduction pathway and increased reliance on the CaMKII subfamily. This increased complexity enables private line communication between Ca(2+) sources at the cell surface and specific cellular targets. Using both new and previously published data, we review the mechanism of a CaMKII-CaM nuclear translocation. This intricatepathway depends on a specific role for multiple Ca(2+)/CaM-dependent kinases and phosphatases: /CaMKII phosphorylates CaMKII to trap CaM; CaN dephosphorylates CaMKII to dispatch it to the nucleus; and PP2A induces CaM release from CaMKII so that CaMKK and CaMKIV can trigger CREB phosphorylation. Thus, while certain basic elements have been conserved from C. elegans, evolutionary modifications offer opportunities for targeted communication, regulation of key nodes and checkpoints, and greater specificity and flexibility in signaling.

Sharma V et al. (2014) Genesis "Recent structural and functional insights into the family of sodium calcium exchangers."

Sharma V, O'Halloran DM

[Genesis, 2014]

Maintenance of calcium homeostasis is necessary for the development and survival of all animals. Calcium ions modulate excitability and bind effectors capable of initiating many processes such as muscular contraction and neurotransmission. However, excessive amounts of calcium in the cytosol or within intracellular calcium stores can trigger apoptotic pathways in cells that have been implicated in cardiac and neuronal pathologies. Accordingly, it is critical for cells to rapidly and effectively regulate calcium levels. The Na(+) /Ca(2+) exchangers (NCX), Na(+) /Ca(2+) /K(+) exchangers (NCKX), and Ca(2+) /Cation exchangers (CCX) are the three classes of sodium calcium antiporters found in animals. These exchanger proteins utilize an electrochemical gradient to extrude calcium. Although they have been studied for decades, much is still unknown about these proteins. In this review, we examine current knowledge about the structure, function, and physiology and also discuss their implication in various developmental disorders. Finally, we highlight recent data characterizing the family of sodium calcium exchangers in the model system, Caenorhabditis elegans, and propose that C. elegans may be an ideal model to complement other systems and help fill gaps in our knowledge of sodium calcium exchange biology.