Rheotaxis Guides Mammalian Sperm Miki, Kiyoshi; Clapham, David E.
CB/Current biology,
03/2013, Volume:
23, Issue:
6
Journal Article
Peer reviewed
Open access
In sea urchins, spermatozoan motility is altered by chemotactic peptides, giving rise to the assumption that mammalian eggs also emit chemotactic agents that guide spermatozoa through the female ...reproductive tract to the mature oocyte. Mammalian spermatozoa indeed undergo complex adaptations within the female (the process of capacitation) that are initiated by agents ranging from pH to progesterone, but these factors are not necessarily taxic. Currently, chemotaxis, thermotaxis, and rheotaxis have not been definitively established in mammals.
Here, we show that positive rheotaxis, the ability of organisms to orient and swim against the flow of surrounding fluid, is a major taxic factor for mouse and human sperm. This flow is generated within 4 hr of sexual stimulation and coitus in female mice; prolactin-triggered oviductal fluid secretion clears the oviduct of debris, lowers viscosity, and generates the stream that guides sperm migration in the oviduct. Rheotaxic movement is demonstrated in capacitated and uncapacitated spermatozoa in low- and high-viscosity media. Finally, we show that a unique sperm motion, which we quantify using the sperm head’s rolling rate, reflects sperm rotation that generates essential force for positioning the sperm in the stream. Rotation requires CatSper channels, presumably by enabling Ca2+ influx.
We propose that rheotaxis is a major determinant of sperm guidance over long distances in the mammalian female reproductive tract. Coitus induces fluid flow to guide sperm in the oviduct. Sperm rheotaxis requires rotational motion during CatSper channel-dependent hyperactivated motility.
► Positive rheotaxis is a major taxic factor for mouse and human sperm ► Sexual stimulation and coitus dramatically increases oviductal fluid secretion ► Rotation balances shear forces for positioning the sperm in the stream ► Rotation requires CatSper calcium-selective ion channels
Calcium Signaling Clapham, David E.
Cell,
12/2007, Volume:
131, Issue:
6
Journal Article
Peer reviewed
Open access
Calcium ions (Ca
2+) impact nearly every aspect of cellular life. This review examines the principles of Ca
2+ signaling, from changes in protein conformations driven by Ca
2+ to the mechanisms that ...control Ca
2+ levels in the cytoplasm and organelles. Also discussed is the highly localized nature of Ca
2+-mediated signal transduction and its specific roles in excitability, exocytosis, motility, apoptosis, and transcription.
Survival in the wild requires organismal adaptations to the availability of nutrients. Endosomes and lysosomes are key intracellular organelles that couple nutrition and metabolic status to cellular ...responses, but how they detect cytosolic ATP levels is not well understood. Here, we identify an endolysosomal ATP-sensitive Na+ channel (lysoNaATP). The channel is a complex formed by two-pore channels (TPC1 and TPC2), ion channels previously thought to be gated by nicotinic acid adenine dinucleotide phosphate (NAADP), and the mammalian target of rapamycin (mTOR). The channel complex detects nutrient status, becomes constitutively open upon nutrient removal and mTOR translocation off the lysosomal membrane, and controls the lysosome’s membrane potential, pH stability, and amino acid homeostasis. Mutant mice lacking lysoNaATP have much reduced exercise endurance after fasting. Thus, TPCs make up an ion channel family that couples the cell’s metabolic state to endolysosomal function and are crucial for physical endurance during food restriction.
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► Lysosomes detect ATP concentration via a Na+ channel formed by TPCs and mTOR ► Two-pore channels (TPCs) are not gated by NAADP ► The Na+ channel (lysoNaATP) detects extracellular nutrients via mTOR ► lysoNaATP regulates lysosomal pH stability and the animal’s fasting endurance
mTOR regulates the flow of sodium through a lysosomal ion channel, lysoNaATP, in response to nutrient levels. lysoNaATP is required for physical endurance during fasting, suggesting that it plays a role in the adaptation to nutrient availability.
TRPM7 is a ubiquitous ion channel and kinase, a unique “chanzyme,” required for proper early embryonic development. It conducts Zn2+, Mg2+, and Ca2+ as well as monovalent cations and contains a ...functional serine/threonine kinase at its carboxyl terminus. Here, we show that in normal tissues and cell lines, the kinase is proteolytically cleaved from the channel domain in a cell-type-specific manner. These TRPM7 cleaved kinase fragments (M7CKs) translocate to the nucleus and bind multiple components of chromatin-remodeling complexes, including Polycomb group proteins. In the nucleus, the kinase phosphorylates specific serines/threonines of histones. M7CK-dependent phosphorylation of H3Ser10 at promoters of TRPM7-dependent genes correlates with their activity. We also demonstrate that cytosolic free Zn2+ is TRPM7 dependent and regulates M7CK binding to transcription factors containing zinc-finger domains. These findings suggest that TRPM7-mediated modulation of intracellular Zn2+ concentration couples ion-channel signaling to epigenetic chromatin covalent modifications that affect gene expression patterns.
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•The ubiquitous chanzyme TRPM7 is cleaved in a cell-type-specific fashion•Cleaved kinase translocate to the nucleus and binds transcription factors•Zinc entry via TRPM7 increases kinase binding to transcription factors•The kinase phosphorylates H3S10, H3S28, and H3T3 to alter transcription
TRPM7-mediated modulation of intracellular Zn2+ couples ion-channel signaling to cleavage and nuclear translocation of its kinase domain, which phosphorylates histones to alter the transcriptional activity of specific genes.
Mammalian two-pore channel proteins (TPC1, TPC2; TPCN1, TPCN2) encode ion channels in intracellular endosomes and lysosomes and were proposed to mediate endolysosomal calcium release triggered by the ...second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP). By directly recording TPCs in endolysosomes from wild-type and TPC double-knockout mice, here we show that, in contrast to previous conclusions, TPCs are in fact sodium-selective channels activated by PI(3,5)P₂ and are not activated by NAADP. Moreover, the primary endolysosomal ion is Na⁺, not K⁺, as had been previously assumed. These findings suggest that the organellar membrane potential may undergo large regulatory changes and may explain the specificity of PI(3,5)P₂ in regulating the fusogenic potential of intracellular organelles.
The exceptionally high temperature sensitivity of certain transient receptor potential (TRP) family ion channels is the molecular basis of hot and cold sensation in sensory neurons. The laws of ...thermodynamics dictate that opening of these specialized TRP channels must involve an unusually large conformational standard-state enthalpy, ΔHo: positive ΔHo for heat-activated and negative ΔHo for cold-activated TRPs. However, the molecular source of such high-enthalpy changes has eluded neurobiologists and biophysicists. Here we offer a general, unifying mechanism for both hot and cold activation that recalls long-appreciated principles of protein folding. We suggest that TRP channel gating is accompanied by large changes in molar heat capacity, ΔCP. This postulate, along with the laws of thermodynamics and independent of mechanistic detail, leads to the conclusion that hot- and cold-sensing TRPs operate by identical conformational changes.
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.
Mitochondria are integral components of cellular calcium (Ca²⁺) signaling. Calcium stimulates mitochondrial adenosine 5'-triphosphate production, but can also initiate apoptosis. In turn, cytoplasmic ...Ca²⁺ concentrations are regulated by mitochondria. Although several transporter and ion-channel mechanisms have been measured in mitochondria, the molecules that govern Ca²⁺ movement across the inner mitochondrial membrane are unknown. We searched for genes that regulate mitochondrial Ca²⁺ and H⁺ concentrations using a genome-wide Drosophila RNA interference (RNAi) screen. The mammalian homolog of one Drosophila gene identified in the screen, Letm1, was found to specifically mediate coupled Ca²⁺/H⁺ exchange. RNAi knockdown, overexpression, and liposome reconstitution of the purified Letm1 protein demonstrate that Letm1 is a mitochondrial Ca²⁺/H⁺ antiporter.
A longstanding hypothesis is that ion channels are present in the membranes of synaptic vesicles and might affect neurotransmitter release. Here we demonstrate that TRPM7, a member of the transient ...receptor potential (TRP) ion channel family, resides in the membrane of synaptic vesicles of sympathetic neurons, forms molecular complexes with the synaptic vesicle proteins synapsin I and synaptotagmin I, and directly interacts with synaptic vesicular snapin. In sympathetic neurons, changes in TRPM7 levels and channel activity alter acetylcholine release, as measured by EPSP amplitudes and decay times in postsynaptic neurons. TRPM7 affects EPSP quantal size, an intrinsic property of synaptic vesicle release. Targeted peptide interference of TRPM7's interaction with snapin affects the amplitudes and kinetics of postsynaptic EPSPs. Thus, vesicular TRPM7 channel activity is critical to neurotransmitter release in sympathetic neurons.
Transient receptor potential (TRP) channels are a large family of ion channel proteins, surpassed in number in mammals only by voltage-gated potassium channels. TRP channels are activated and ...regulated through strikingly diverse mechanisms, making them suitable candidates for cellular sensors. They respond to environmental stimuli such as temperature, pH, osmolarity, pheromones, taste, and plant compounds, and intracellular stimuli such as Ca(2+) and phosphatidylinositol signal transduction pathways. However, it is still largely unknown how TRP channels are activated in vivo. Despite the uncertainties, emerging evidence using TRP channel knockout mice indicates that these channels have broad function in physiology. Here we review the recent progress on the physiology, pharmacology and pathophysiological function of mammalian TRP channels.
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