Rivers of Indochina as potential drivers of lineage diversification in the spotted flying lizard (Draco maculatus) species complex.

Southeast Asia hosts a rich concentration of biodiversity within multiple biodiversity hotspots. Indochina, a region with remarkably high levels of in situ diversification, possesses five major rivers (Ayeyarwady, Chiang Mai, Mekong, Red, and Salween), several of which coincide with phylogenetic breaks of terrestrial taxa. Draco maculatus possesses a range that stretches across Indochina, which widespread geographic distribution along with potential discrete variation within subspecies alludes to the possibility of this taxon constituting multiple divergent lineages. Using sequence data from three mitochondrial (12S, 16S, and ND2) and three nuclear (BDNF, CMOS, and PNN) genes, we provide the first estimated phylogeny of this hypothesized species complex and examine its phylogeographic architecture with maximum likelihood and Bayes factor delimitation (BFD) approaches. Our results support multiple divergent lineages with phylogenetic breaks coincident with rivers, indicating that river barriers may be contributing to the elevated levels of in situ diversification of Indochina.

Unraveling the systematics and evolution of the 'Geophagus' brasiliensis (Cichliformes: Cichlidae) species complex.

The 'Geophagus' brasiliensis complex is one of the most abundant groups of cichlids from eastern coastal basins in South America. Traditionally, this fish group has been recognized as incertae sedis because of phylogenetic uncertainties and unclear taxonomy. In addition, the remarkable morphological, chromosomal, and DNA variation reported over recent years in several populations of these cichlids has increased the debate about their species richness and their distributional range. Here, we tested the presence of independent evolutionary lineages within the 'G.' brasiliensis complex, addressing their taxonomic status and evolutionary relationships, including a comparative analysis of genetic and morphological patterns, based on an extensive dataset, comprising 172 sampling sites along most of their known range using a mitochondrial marker, RADseq data and geometric morphometrics. The number of putative species in the present study varied from 9 to 11 depending on the molecular species delimitation methods used. Our results revealed at least two putative new taxa ('Geophagus' sp. Doce and 'Geophagus' sp. Upper Contas). Morphometric analyses, particularly those based on Canonical Variate Analysis (CVA), revealed significant morphological differentiation between species within the main clades. On the other hand, analyses of morphological phylogenetic signal and phylomorphospace provided no evidence of adaptive differentiation among these species. Thus, diversification in the 'G.' brasiliensis complex seems to have been influenced by hydrogeological events that promoted allopatry, such as the presence of paleodrainages and distributional reconfiguration through river captures. We propose major changes in the known distribution of some species within the complex and conservatively suggest the recognition of 10 species within the 'Geophagus' brasiliensis complex, with the potential for further dividing 'G.' rufomarginatus after additional taxonomic evaluation.

Synteny and phylogenetic analysis of paralogous thyrostimulin beta subunits (GpB5) in vertebrates.

At some point early in the vertebrate lineage, two whole genome duplication events (1R, 2R) took place that allowed for the diversification and sub-/neo-functionalization of the glycoprotein hormones (GpHs). All jawed vertebrates possess the GpHs luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH), each of which are heterodimers with a common alpha subunit and unique beta subunits. In 2002, a novel glycoprotein hormone named thyrostimulin was described to have unique GpA2 and GpB5 subunits that were homologous to the vertebrate alpha and beta subunits. The presence of GpA2 and GpB5 in representative protostomes and deuterostomes indicates their ancestry in the GpH family. There are several reports of GpH subunit evolution, but none have included GpA2 and GpB5 for species in each major vertebrate class. Thus, we addressed the ancestry of two paralogous GpB5 subunits (GpB5a and GpB5b) that were previously only recognized in two teleost species. Our search for orthologous GpB5a and GpB5b sequences in representative vertebrates and phylogenetic analysis, in addition to the currently published evolutionary scenarios of the GpH family, supports that GpB5a and GpB5b are paralogs that arose from the first vertebrate whole genome duplication event (1R). Syntenic analysis supports lineage specific losses of GpB5a in chondrichthyes, basal actinopterygians, and tetrapods, and retention in coelacanth and teleosts. Additionally, we were unable to identify GpA2 transcripts from tilapia mRNA, suggesting that this species does not produce heterodimeric thyrostimulin. While the conserved or even species-specific functional role of thyrostimulin or its individual subunits are still unknown in vertebrates, the analyses presented here provide context for future studies on the functional divergence of the GpH family.

Human brain transcriptome analysis finds region- and subject-specific expression signatures of GABAAR subunits.

Altered expression of GABA receptors (GABAARs) has been implicated in neurological and psychiatric disorders, but limited information about region-specific GABAAR subunit expression in healthy human brains, heteromeric assembly of major isoforms, and their collective organization across healthy individuals, are major roadblocks to understanding their role in non-physiological states. Here, by using microarray and RNA-Seq datasets-from single cell nuclei to global brain expression-from the Allen Institute, we find that transcriptional expression of GABAAR subunits is anatomically organized according to their neurodevelopmental origin. The data show a combination of complementary and mutually-exclusive expression patterns that delineate major isoforms, and which is highly stereotypical across brains from control donors. We summarize the region-specific signature of GABAR subunits per subject and its variability in a control population sample that can be used as a reference for remodeling changes during homeostatic rearrangements of GABAAR subunits after physiological, pharmacological or pathological challenges.

Cytochrome C Oxidase Subunit 1, Internal Transcribed Spacer 1, Nicotinamide Adenine Dinucleotide Hydrogen Dehydrogenase Subunits 2 and 5 of Clonorchis sinensis Ancient DNA Retrieved from Joseon Dynasty Mummy Specimens.

We analyzed Clonorchis sinensis ancient DNA (aDNA) acquired from the specimens of the Joseon mummies. The target regions were cytochrome C oxidase subunit 1 (CO1), internal transcribed spacer 1 (ITS1), nicotinamide adenine dinucleotide hydrogen (NADH) dehydrogenase subunits 2 (NAD2) and 5 (NAD5). The sequences of C. sinensis aDNA was completely or almost identical to modern C. sinensis sequences in GenBank. We also found that ITS1, NAD2 and NAD5 could be good markers for molecular diagnosis between C. sinensis and the other trematode parasite species. The current result could improve our knowledge about genetic history of C. sinensis.

Uncovered variability in olive moth (Prays oleae) questions species monophyly.

The olive moth -Prays oleae Bern.- remains a significant pest of olive trees showing situation dependent changes in population densities and in severity of damages. The genetic variability of olive moth was assessed on three main olive orchards regions in Portugal by three different markers (COI, nad5 and RpS5), suggesting high species diversity albeit with no obvious relation with a regional pattern nor to an identified ecological niche. Selected COI sequences obtained in this study were combined with those available in the databases for Prays genus to generate a global dataset. The reconstruction of the Prays phylogeny based on this marker revealed the need to revise Prays oleae to confirm its status of single species: COI data suggests the co-existence of two sympatric evolutionary lineages of morphologically cryptic olive moth. We show, however, that the distinct mitochondrial subdivision observed in the partial COI gene fragment is not corroborated by the other DNA sequences. There is the need of understanding this paradigm and the extent of Prays variability, as the disclosure of lineage-specific differences in biological traits between the identified lineages is fundamental for the development of appropriate pest management practices.

Southernmost records of Escarpia spicata and Lamellibrachia barhami (Annelida: Siboglinidae) confirmed with DNA obtained from dried tubes collected from undiscovered reducing environments in northern Chile.

Deep-sea fishing bycatch enables collection of samples of rare species that are not easily accessible, for research purposes. However, these specimens are often degraded, losing diagnostic morphological characteristics. Several tubes of vestimentiferans, conspicuous annelids endemic to chemosynthetic environments, were obtained from a single batch of deep-sea fishing bycatch at depths of around 1,500 m off Huasco, northern Chile, as part of an ongoing study examining bycatch species. DNA sequences of the mitochondrial cytochrome c oxidase subunit I (COI) gene and an intron region within the hemoglobin subunit B2 (hbB2i) were successfully determined using vestimentiferans' dried-up tubes and their degraded inner tissue. Molecular phylogenetic analyses based on DNA sequence identified the samples as Escarpia spicata Jones, 1985, and Lamellibrachia barhami Webb, 1969. These are the southernmost records, vastly extending the geographical ranges of both species from Santa Catalina Island, California to northern Chile for E. spicata (over 8,000 km), and from Vancouver Island Margin to northern Chile for L. barhami (over 10,000 km). We also determined a 16S rRNA sequence of symbiotic bacteria of L. barhami. The sequence of the bacteria is the same as that of E. laminata, Lamellibrachia sp. 1, and Lamellibrachia sp.2 known from the Gulf of Mexico. The present study provides sound evidence forthe presence of reducing environments along the continental margin of northern Chile.

A genomic perspective of the pink-headed duck Rhodonessa caryophyllacea suggests a long history of low effective population size.

The first molecular phylogenetic hypothesis for the possibly extinct pink-headed duck Rhodonessa caryophyllacea unambiguously shows that it belongs to the pochard radiation that also includes the genera Aythya and Netta. It is the sister to all modern-day pochards and belongs to a lineage that branched off from the others more than 2.8 million years ago. Rhodonessa caryophyllacea is believed to never have been common in modern time and we show this has probably been the situation for as long as 100,000 years. Our results suggest that their effective population size varied between 15,000 and 25,000 individuals during the last 150,000 years of the Pleistocene. The reasons behind this are largely unknown as very little is known about the life-history and biology of this species. Presumably it is due to factors related to feeding or to breeding, but we may never know this for sure.

Photosynthetic Trichomes Contain a Specific Rubisco with a Modified pH-Dependent Activity.

Ribulose-1,5-biphosphate carboxylase/oxygenase (Rubisco) is the most abundant enzyme in plants and is responsible for CO2 fixation during photosynthesis. This enzyme is assembled from eight large subunits (RbcL) encoded by a single chloroplast gene and eight small subunits (RbcS) encoded by a nuclear gene family. Rubisco is primarily found in the chloroplasts of mesophyll (C3 plants), bundle-sheath (C4 plants), and guard cells. In certain species, photosynthesis also takes place in the secretory cells of glandular trichomes, which are epidermal outgrowths (hairs) involved in the secretion of specialized metabolites. However, photosynthesis and, in particular, Rubisco have not been characterized in trichomes. Here, we show that tobacco (Nicotiana tabacum) trichomes contain a specific Rubisco small subunit, NtRbcS-T, which belongs to an uncharacterized phylogenetic cluster (T). This cluster contains RbcS from at least 33 species, including monocots, many of which are known to possess glandular trichomes. Cluster T is distinct from the cluster M, which includes the abundant, functionally characterized RbcS isoforms expressed in mesophyll or bundle-sheath cells. Expression of NtRbcS-T in Chlamydomonas reinhardtii and purification of the full Rubisco complex showed that this isoform conferred higher Vmax and Km values as well as higher acidic pH-dependent activity than NtRbcS-M, an isoform expressed in the mesophyll. This observation was confirmed with trichome extracts. These data show that an ancient divergence allowed for the emergence of a so-far-uncharacterized RbcS cluster. We propose that secretory trichomes have a particular Rubisco uniquely adapted to secretory cells where CO2 is released by the active specialized metabolism.

Developmental and Regulatory Functions of Na(+) Channel Non-pore-forming ß Subunits.

Voltage-gated Na(+) channels (VGSCs) isolated from mammalian neurons are heterotrimeric complexes containing one pore-forming α subunit and two non-pore-forming ß subunits. In excitable cells, VGSCs are responsible for the initiation of action potentials. VGSC ß subunits are type I topology glycoproteins, containing an extracellular amino-terminal immunoglobulin (Ig) domain with homology to many neural cell adhesion molecules (CAMs), a single transmembrane segment, and an intracellular carboxyl-terminal domain. VGSC ß subunits are encoded by a gene family that is distinct from the α subunits. While α subunits are expressed in prokaryotes, ß subunit orthologs did not arise until after the emergence of vertebrates. ß subunits regulate the cell surface expression, subcellular localization, and gating properties of their associated α subunits. In addition, like many other Ig-CAMs, ß subunits are involved in cell migration, neurite outgrowth, and axon pathfinding and may function in these roles in the absence of associated α subunits. In sum, these multifunctional proteins are critical for both channel regulation and central nervous system development.

Phylogenomic Analysis of Type 1 NADH:Quinone Oxidoreductase.

We performed phylogenomic analysis of the catalytic core of NADH:quinone oxidoreductases of type 1 (NDH-1). Analysis of phylogenetic trees, as constructed for the core subunits of NDH-1, revealed fundamental differences in their topologies. In the case of four putatively homologous ion-carrying membrane subunits, the trees for the NuoH and NuoN subunits contained separate archaeal clades, whereas subunits NuoL and NuoM were characterized by multiple archaeal clades spread among bacterial branches. Large, separate clades, which united sequences belonging to different archaeal subdomains, were also found for cytoplasmic subunits NuoD and NuoB, homologous to the large and small subunits of nickel-iron hydrogenases. A smaller such clade was also shown for subunit NuoC. Based on these data, we suggest that the ancestral NDH-1 complex could be present already at the stage of the Last Universal Cellular Ancestor (LUCA). Ancestral forms of membrane subunits NuoN and NuoH and cytoplasmic subunits NuoD, NuoB, and, perhaps NuoC, may have formed a membrane complex that operated as an ion-translocating membrane hydrogenase. After the complex attained the ability to reduce membrane quinones, gene duplications could yield the subunits NuoL and NuoM, which enabled translocation of additional ions.

Comparative analyses of quaternary arrangements in homo-oligomeric proteins in superfamilies: Functional implications.

A comprehensive analysis of the quaternary features of distantly related homo-oligomeric proteins is the focus of the current study. This study has been performed at the levels of quaternary state, symmetry, and quaternary structure. Quaternary state and quaternary structure refers to the number of subunits and spatial arrangements of subunits, respectively. Using a large dataset of available 3D structures of biologically relevant assemblies, we show that only 53% of the distantly related homo-oligomeric proteins have the same quaternary state. Considering these homologous homo-oligomers with the same quaternary state, conservation of quaternary structures is observed only in 38% of the pairs. In 36% of the pairs of distantly related homo-oligomers with different quaternary states the larger assembly in a pair shows high structural similarity with the entire quaternary structure of the related protein with lower quaternary state and it is referred as "Russian doll effect." The differences in quaternary state and structure have been suggested to contribute to the functional diversity. Detailed investigations show that even though the gross functions of many distantly related homo-oligomers are the same, finer level differences in molecular functions are manifested by differences in quaternary states and structures. Comparison of structures of biological assemblies in distantly and closely related homo-oligomeric proteins throughout the study differentiates the effects of sequence divergence on the quaternary structures and function. Knowledge inferred from this study can provide insights for improved protein structure classification and function prediction of homo-oligomers. Proteins 2016; 84:1190-1202. © 2016 Wiley Periodicals, Inc.

Multiple Forms of Human DNA Polymerase Delta Sub-Assembling in Cellular DNA Transactions.

Among three major replicative DNA polymerases of the B-family, Pol α, Pol δ and Pol ε, Pol δ plays an essential role in chromosomal DNA replication and is also involved in various DNA repair processes in eukaryotes. Human Pol δ is commonly viewed as a heterotetrameric complex, consisting of the catalytic subunit p125 and second subunit p50, together with two additional accessory subunits, p68 and p12. A growing body of research has shown that the latter subunits play a critical role in the regulation of Pol δ functions. The formation of a new form of Pol δ, heterotrimer Pol δ3, is found by virtue of the depletion of p12 through the ubiquitin-proteasome pathway in response to DNA damages that are trigged by UV irradiation, alkylating agents, oxidative and replication stresses. Pol δ3 exhibits significant differences in properties to its progenitor with a major impact on cellular processes in genomic surveillance, DNA replication and DNA repair. Our recent studies indicate that there exists an alternative pathway for Pol δ3 formation by calpain-mediated proteolysis of p12 in a calcium-triggered apoptosis in living cells. In this article, we review and discuss the recent advances from our group and others in the studies of human Pol δ with an emphasis on the generation of its multiple forms by reconstitution and subsequent alternations in enzymatic properties, the multiple pathways of the Pol δ3 formation in living cells, and the phylogenetic analysis of the evolutionary history on POLD4 gene that is for the p12 subunit.

The role of class I, II and III PI 3-kinases in platelet production and activation and their implication in thrombosis.

Blood platelets play a pivotal role in haemostasis and are strongly involved in arterial thrombosis, a leading cause of death worldwide. Besides their critical role in pathophysiology, platelets represent a valuable model to investigate, both in vitro and in vivo, the biological roles of different branches of the phosphoinositide metabolism, which is highly active in platelets. While the phospholipase C (PLC) pathway has a crucial role in platelet activation, it is now well established that at least one class I phosphoinositide 3-kinase (PI3K) is also mandatory for proper platelet functions. Except class II PI3Kγ, all other isoforms of PI3Ks (class I α, ß, γ, δ; class II α, ß and class III) are expressed in platelets. Class I PI3Ks have been extensively studied in different models over the past few decades and several isoforms are promising drug targets to treat cancer and immune diseases. In platelet activation, it has been shown that while class I PI3Kδ plays a minor role, class I PI3Kß has an important function particularly in thrombus growth and stability under high shear stress conditions found in stenotic arteries. This class I PI3K is a potentially interesting target for antithrombotic strategies. The role of class I PI3Kα remains ill defined in platelets. Herein, we will discuss our recent data showing the potential impact of inhibitors of this kinase on thrombus formation. The role of class II PI3Kα and ß as well as class III PI3K (Vps34) in platelet production and function is just emerging. Based on our data and those very recently published in the literature, we will discuss the impact of these three PI3K isoforms in platelet production and functions and in thrombosis.

[ATP-sensitive K(+)-channels in muscle cells: features and physiological role].

ATP-sensitive K(+)-channels of plasma membranes belong to the inward rectifier potassium channels type. They are involved in coupling of electrical activity of muscle cell with its metabolic state. These channels are heterooctameric and consist of two types of subunits: four poreforming (Kir 6.x) and four regulatory (SUR, sulfonylurea receptor). The Kir subunits contain highly selective K+ filter and provide for high-velocity K+ currents. The SUR subunits contain binding sites for activators and blockers and have metabolic sensor, which enables channel activation under conditions of metabolic stress. ATP blocks K+ currents through the ATP-sensitive K(+)-channels in the most types of muscle cells. However, functional activity of these channels does not depend on absolute concentration of ATP but on the ATP/ADP ratio and presence of Mg2+. Physiologically active substances, such as phosphatidylinositol bisphosphate and fatty acid esters can regulate the activity of these structures in muscle cells. Activation of these channels under ischemic conditions underlies their cytoprotective action, which results in prevention of Ca2+ overload in cytosol. In contrast to ATP-sensitive K(+)-channels of plasma membranes, the data regarding the structure and function of ATP-sensitive K(+)-channels of mitochondrial membrane are contradictory. Pore-forming subunits of this channel have not been firmly identified yet. ATP-sensitive K+ transport through the mitochondrial membrane is easily tested by different methods, which are briefly reviewed in this paper. Interaction of mitoK(ATP) with physiological and pharmacological ligands is discussed as well.

[Structure and functions of glutathione transferases].

Data about classification, nomenclature, structure, substrate specificity and role of many glutathione transferase's isoenzymes in cell functions have been summarised. The enzyme has been discovered more than 50 years ago. This family of proteins is updated continuously. It has very different composition and will have demand for system analysis for many years.

Cleavage site and Ectodomain of HA2 sub-unit sequence of three equine influenza virus isolated in Morocco.

BACKGROUND: The equine influenza (EI) is an infectious and contagious disease of the upper respiratory tract of horses. Two outbreaks were notified in Morocco during 1997 and 2004 respectively in Nador and Essaouira. The aims of the present study concern the amino acids sequences comparison with reference strain A/equine/Miami/1963(H3N8) of the HA2 subunit including the cleavage site of three equine influenza viruses (H3N8) isolated in Morocco: A/equine/Nador/1/1997(H3N8), A/equine/Essaouira/2/2004 (H3N8) and A/equine/Essaouira/3/2004 (H3N8). RESULTS: The obtained results demonstrated that the substitutions were located at Ectodomain (ED) and transmembrane domain (TD), and they have only one arginine in cleavage site (HA1-PEKQI-R329-GI-HA2). In the Ectodomain, the mutation N/1542/T deleted the NGT glycosylation site at position 154 for both strains A/equine/Essaouira/2/2004(H3N8) and A/equine/Essaouira/3/2004(H3N8). Except for mutation D/1602/Y of the A/equine/Nador/1/1997(H3N8) strain, the other mutations were involved in non conserved sites. While the transmembrane domain (TM) of the strain A/equine/Essaouira/3/2004(H3N8) exhibits a substitution at residue C/1992/F. For the A/equine/Nador/1/1997(H3N8) strain the HA2 shows a mutation at residue M/2072/L. Three Moroccan strains reveals a common substitution at the residue E/2112/Q located between transmembrane domain TM and the cytoplasmic domain (CD). CONCLUSION: The given nature virulence of three Moroccan strains, the identified and reported mutations certainly played a permissive role of infection viral process.

Unique subunit packing in mycobacterial nanoRNase leads to alternate substrate recognitions in DHH phosphodiesterases.

DHH superfamily includes RecJ, nanoRNases (NrnA), cyclic nucleotide phosphodiesterases and pyrophosphatases. In this study, we have carried out in vitro and in vivo investigations on the bifunctional NrnA-homolog from Mycobacterium smegmatis, MSMEG_2630. The crystal structure of MSMEG_2630 was determined to 2.2-Å resolution and reveals a dimer consisting of two identical subunits with each subunit folding into an N-terminal DHH domain and a C-terminal DHHA1 domain. The overall structure and fold of the individual domains is similar to other members of DHH superfamily. However, MSMEG_2630 exhibits a distinct quaternary structure in contrast to other DHH phosphodiesterases. This novel mode of subunit packing and variations in the linker region that enlarge the domain interface are responsible for alternate recognitions of substrates in the bifunctional nanoRNases. MSMEG_2630 exhibits bifunctional 3'-5' exonuclease [on both deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) substrates] as well as CysQ-like phosphatase activity (on pAp) in vitro with a preference for nanoRNA substrates over single-stranded DNA of equivalent lengths. A transposon disruption of MSMEG_2630 in M. smegmatis causes growth impairment in the presence of various DNA-damaging agents. Further phylogenetic analysis and genome organization reveals clustering of bacterial nanoRNases into two distinct subfamilies with possible role in transcriptional and translational events during stress.

Protein flexibility facilitates quaternary structure assembly and evolution.

The intrinsic flexibility of proteins allows them to undergo large conformational fluctuations in solution or upon interaction with other molecules. Proteins also commonly assemble into complexes with diverse quaternary structure arrangements. Here we investigate how the flexibility of individual protein chains influences the assembly and evolution of protein complexes. We find that flexibility appears to be particularly conducive to the formation of heterologous (i.e., asymmetric) intersubunit interfaces. This leads to a strong association between subunit flexibility and homomeric complexes with cyclic and asymmetric quaternary structure topologies. Similarly, we also observe that the more nonhomologous subunits that assemble together within a complex, the more flexible those subunits tend to be. Importantly, these findings suggest that subunit flexibility should be closely related to the evolutionary history of a complex. We confirm this by showing that evolutionarily more recent subunits are generally more flexible than evolutionarily older subunits. Finally, we investigate the very different explorations of quaternary structure space that have occurred in different evolutionary lineages. In particular, the increased flexibility of eukaryotic proteins appears to enable the assembly of heteromeric complexes with more unique components.

KCa and Ca(2+) channels: the complex thought.

Potassium channels belong to the largest and the most diverse super-families of ion channels. Among them, Ca(2+)-activated K(+) channels (KCa) comprise many members. Based on their single channel conductance they are divided into three subfamilies: big conductance (BKCa), intermediate conductance (IKCa) and small conductance (SKCa; SK1, SK2 and SK3). Ca(2+) channels are divided into two main families, voltage gated/voltage dependent Ca(2+) channels and non-voltage gated/voltage independent Ca(2+) channels. Based on their electrophysiological and pharmacological properties and on the tissue where there are expressed, voltage gated Ca(2+) channels (Cav) are divided into 5 families: T-type, L-type, N-type, P/Q-type and R-type Ca(2+). Non-voltage gated Ca(2+) channels comprise the TRP (TRPC, TRPV, TRPM, TRPA, TRPP, TRPML and TRPN) and Orai (Orai1 to Orai3) families and their partners STIM (STIM1 to STIM2). A depolarization is needed to activate voltage-gated Ca(2+) channels while non-voltage gated Ca(2+) channels are activated by Ca(2+) depletion of the endoplasmic reticulum stores (SOCs) or by receptors (ROCs). These two Ca(2+) channel families also control constitutive Ca(2+) entries. For reducing the energy consumption and for the fine regulation of Ca(2+), KCa and Ca(2+) channels appear associated as complexes in excitable and non-excitable cells. Interestingly, there is now evidence that KCa-Ca(2+) channel complexes are also found in cancer cells and contribute to cancer-associated functions such as cell proliferation, cell migration and the capacity to develop metastases. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.