cAMP Activation Research Articles

Acquisition of Arabic Language based on Stephen Krashen's Theory in the Arabic Camp Activities

The determining factors for a person's success in language vary widely. One of them is the acquisition of a person's language which is a source of skill in producing the language itself. There is often a contradiction between the terms language acquisition and language learning. Psycholinguistics experts view that language acquisition only occurs for the first language, but this is different from Stephen Khrasen who stated that language acquisition can be obtained for foreign languages. On this basis, researchers studied the implementation of foreign language acquisition at MAN 1 Padang during the Arabic Camp activity, based on Stephen Khrasen's theory. Researchers used a qualitative approach with a case study research design. Data collection includes observation, interviews and documentation with data analysis techniques using data triangulation. The results showed that the acquisition of a second language was influenced by good input and processes such as the all-day language environment and good monitoring processes from the tutors. All of this is in accordance with Stephen Khrasen's theory which will provide maximum output in producing Arabic like native speakers even though it is still in a simple sentence formation system in the Camp environment.

MARKIAN TERLETSKYI IN THE CULTURAL AND EDUCATIONAL ENVIRONMENT OF GALICIA AND CZECHOSLOVAKIA DURING THE 20 – 30-ies OF THE XXth CENTURY

The purpose of the research is to analyze Markiyan Terletskyi’s participation in the cultural and educational environment of Galicia (Halychyna) (1920 – 1930) and to highlight the main aspects of his activities in camps for the interned Ukrainian servicemen in Czechoslovakia, as well as in the Ukrainian educational institutions in Podyebrad and Prague. The methodology of the research is based on the principles of historicism, systematicity, scientificity; as well as the use of general scientific and special historical methods. Owing to the application of the biographical method, the author highlighted M. Terletskyi’s activities and defined the place and role in the educational institutions of Przemysl, Podyebrad, Prague, Yavoriv and Stanislaviv (nowadays Ivano-Frankivsk), as well as in the Czechoslovak camps for the interned Ukrainian soldiers. The scientific novelty is that for the first time in the Ukrainian historiography, based on the analysis of a set of sources, M. Terletskyi’s biography and his cultural and educational activities were reconstructed. The Conclusions. Having analyzed M. Terletskyi’s multifaceted activities, we make bold to say that he was primarily closely associated with the socio-cultural environment in Przemysl, which manifested itself in his pedagogical work in the Ukrainian schools primarily. M. Terletskyi’s several years of multifaceted work in the camps for the interned Ukrainian soldiers in Czechoslovakia was aimed at raising their cultural and educational level primarily. The research and teaching work in the Ukrainian educational emigration institutions of the Czechoslovak Republic testified to his active civic position. After his return to Galicia (Halychyna), M. Terletskyi joined the native schools’ activities. Based on the analysis of his pedagogical activity, scientific and pedagogical research, speeches at pedagogical meetings, meetings in educational societies, M. Terletskyi’s role in the Ukrainian national school and education development was clarified.

MiR‑142‑3p targets AC9 to regulate sciatic nerve injury‑induced neuropathic pain by regulating the cAMP/AMPK signalling pathway.

The aim of the present study was to investigate the effects of microRNA (miR)-142-3p on neuropathic pain caused by sciatic nerve injury in chronic compression injury (CCI) rats, and further investigate its mechanism. Rat experiments were divided into four parts in the study. In the first part, the rats were divided into the Sham and CCI groups. The expression of miR-142-3p, AC9 and cAMP were detected. In the second part, the rats were divided into the Sham, CCI, miR-142-3p mimic, mimic-negative control (NC), miR-142-3p small interfering RNA (siRNA) and siRNA-NC groups. The expression of cAMP and the levels of AMPK pathway-related proteins were detected. In the third part, the rats were randomly divided into Sham, CCI, AC9 mimic, mi-NC, AC9 siRNA and si-NC groups. Double luciferase reporter assay was used to analyse the targeting relationship between miR-142-3p and AC9. In the fourth part, the rats were divided into the Sham, CCI, miR-142-3p siRNA, AC9 mimic, miR-142-3p siRNA + AC9 siRNA, cAMP activator (Forskolin) and miR-142-3p siRNA + cAMP inhibitor groups. The expres-sion of miR-142-3p was significantly increased while AC9 and cAMP expression significantly decreased in CCI rats. However, AC9 overexpression significantly increased the levels of cAMP protein. Luciferase reporter assay also proved that AC9 is the target gene of miR-142-3p. Moreover, miR-142-3p silencing was found to reduce neuropathic pain in CCI rats by upregulating the expression of AC9. It was also found that cAMP activation can relieve neuropathic pain and promote the expression of AMPK-related proteins in CCI rats. Silencing miR-142-3p can target AC9 to reduce the expression of inflammatory factors and neuropathic pain in CCI rats by increasing the expression of cAMP/AMPK pathway-related proteins.

Youth program activity impacts: A model of camp activities, psychological needs, and immersion

We examined linkages through which structured camp experiences may facilitate satisfaction of psychological needs and thereby contribute to expansion of the self. First, we tested the effects of “leveling-up” the challenges of activities with the skills of campers and camper motivation source (intrinsic, integrated, introjected, and extrinsic) on immediate psychological need satisfaction during each of eight camp activities (archery, crafts, dancing, fishing, kayaking, riflery, rock wall climbing, and swimming). Then, we tested relations between psychological need satisfaction and the subjective experience, immersion. Immersion, theoretically, yields expansion of the self. Campers (n = 150, ages 11–13, co-recreational) reported their sense of autonomy, competence, and relatedness, and degree of immersion immediately following each of the eight camp activities. The hypothesized causal sequences were supported by the data. Camper motivation source and leveling-up the challenge-skill structure of immediate camp experiences yielded psychological need satisfaction. Psychological need satisfaction, in turn, increased immersion.

Modeling areal measures of campsite impacts on the Appalachian National Scenic Trail to enhance ecological sustainability

Campsite impacts in protected natural areas are most effectively minimized by a containment strategy that focuses use on a limited number of sustainable campsites that spatially concentrate camping activities. This research employs spatial autoregressive (SAR) modeling to evaluate the relative influence of use-related, environmental, and managerial factors on two salient measures of campsite impact. Relational analyses examined numerous field-collected and GIS-derived indicators, including several new indicators calculated using high-resolution Light Detection and Ranging (LiDAR) topographic data to evaluate the influence of terrain characteristics on the dependent variables.Chosen variables in the best SAR models explained 35% and 30% of the variation in campsite size and area of vegetation loss on campsites. Results identified three key indicators that managers can manipulate to enhance the sustainability of campsites: campsite type, and terrain characteristics relating to landform slope and topographic roughness. Results support indirect management methods that rely on the location, design, construction, and maintenance of campsites, instead of direct regulations that restrict visitation or visitor freedoms. As visitation pressures continue to increase, this knowledge can be applied to select and promote the use of more ecologically sustainable campsites.

MENINGKATKAN KEMAMPUAN BERBICARA BAHASA INGGRIS DASAR MELALUI KEGIATAN ENGLISH CAMP

This study aims to improve the English speaking skills of STKIP MB students majoring in elementary school teacher education who take English courses, especially speaking skills at the basic level through English camp activities. English camp activities are outdoor activities carried out as practical speaking activities outside the classroom. . This activity is carried out after the lecture enters the midterm exam where students have first learned the basic theory for seven meetings at the beginning of the lecture. This research is a classroom action research conducted in two cycles with each cycle consisting of two meetings of English camp activities. The results of this study show their speaking ability at the basic level with the topics that have been determined increases significantly each meeting and at the end of each cycle taken from the speaking ability data with categories of assessment of topic accuracy, use of vocabulary, pronunciation and fluency in speaking. . The conclusion in the study shows that English camp activities can improve basic level speaking skills for PGSD STKIP MB students with success indicators of 80% of students getting an oral speaking exam score of 75 or more

Aperto per ferie: third spaces meet pastoral contexts

Abstract Media education is a cultural framework that can be applied in different contexts: schools, families, informal educational environments, along with pastoral work. With Pope Francis’ championing, there is an increasing need to bridge pastoral care and the media, which can become new important forms of proximity and open opportunities to connect and assume responsibility towards others. Our aim is to understand how parishes can think of themselves as third spaces. The paper tackles this question through the exploration of the initiative Aperto per ferie. The initiative was created to enable professionals to experience the summer camp activities despite the Covid-19 pandemic, finding new ways of aggregation in pastoral youth clubs and taking advantage of digital community meetings. It developed a digital space to promote a unifying experience. With digital technologies, the boundaries of the community are redrawn. The correspondence with the territory (of the parish and the diocese) is no longer pre-determined. A community with porous edges is making its way and is more open and permeable to contributions coming from outside, and perhaps more accessible, even by those who do not frequent parish environments.

Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits.

cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.

Geomorphological analysis of the San Domino Island (Tremiti Islands, Southern Adriatic Sea). Results from the 2019 Geomorphological Field Camp of the MSc in Geological Science and Technology (University of Chieti-Pescara)

ABSTRACT The 2019 Geomorphological Field Camp at San Domino Island (Tremiti Islands, Southern Adriatic Sea) is the result of geological and geomorphological field work activities carried out by a group of students attending the Geomorphological field mapping course of the Master’s Degree in Geological Science and Technology (University of Chieti-Pescara). The main map (1:5000 scale) was obtained through an integrated approach that incorporates morphometric analysis, geological and geomorphological field mapping, and geomorphological profiles drawing. Activities were carried out by all students, divided into six working groups of three to four persons each. The field camp and field work activities made it possible to produce a detailed thematic map, as a scientific tool to depict the San Domino Island landscape, and to outline some geomorphological issues in terms of possible constraints to landscape evolution, geomorphological processes distribution, and natural hazard assessment.

Making Apps

In response to the need to broaden participation in computer science, we designed a summer camp to teach middle-school-aged youth to code apps with MIT App Inventor. For the past four summers, we have observed significant gains in youth's interest and self-efficacy in computer science, after attending our camps. The majority of these youth, however, were youth from our local community. To provide equal access across the state and secure more diversity, we were interested in examining the effect of the camp on a broader population of youth. Thus, we partnered with an outreach program to reach and test our camps on youth from low-income high-poverty areas in the Intermountain West. During the summer of 2019, we conducted two sets of camps: locally advertised app camps that attracted youth from our local community and a second set of camps as part of a larger outreach program for youth from low-income high-poverty areas. The camps for both populations followed the same design of personnel, camp activities, structure, and curriculum. However, the background of the participants was slightly different. Using survey data, we found that the local sample experienced significant gains in both self-efficacy and interest, while the outreach group only reported significant gains in self-efficacy after attending the camp. However, the qualitative data collected from the outreach participants indicated that they had a positive experience both with the camp and their mentors. In this article, we discuss the camp design and findings in relation to strategies for broadening participation in Computer Science education.

Genetic Basis Underlying the Hyperhemolytic Phenotype of Streptococcus agalactiae Strain CNCTC10/84.

Streptococcus agalactiae (group B streptococcus [GBS]) is a major cause of infections in newborns, pregnant women, and immunocompromised patients. GBS strain CNCTC10/84 is a clinical isolate that has high virulence in animal models of infection and has been used extensively to study GBS pathogenesis. Two unusual features of this strain are hyperhemolytic activity and hypo-CAMP factor activity. These two phenotypes are typical of GBS strains that are functionally deficient in the CovR-CovS two-component regulatory system. A previous whole-genome sequencing study found that strain CNCTC10/84 has intact covR and covS regulatory genes. We investigated CovR-CovS regulation in CNCTC10/84 and discovered that a single-nucleotide insertion in a homopolymeric tract in the covR promoter region underlies the strong hemolytic activity and weak CAMP activity of this strain. Using isogenic mutant strains, we demonstrate that this single-nucleotide insertion confers significantly decreased expression of covR and covS and altered expression of CovR-CovS-regulated genes, including that of genes encoding β-hemolysin and CAMP factor. This single-nucleotide insertion also confers significantly increased GBS survival in human whole blood ex vivoIMPORTANCE Group B streptococcus (GBS) is the leading cause of neonatal sepsis, pneumonia, and meningitis. GBS strain CNCTC10/84 is a highly virulent blood isolate that has been used extensively to study GBS pathogenesis for over 20 years. Strain CNCTC10/84 has an unusually strong hemolytic activity, but the genetic basis is unknown. In this study, we discovered that a single-nucleotide insertion in an intergenic homopolymeric tract is responsible for the elevated hemolytic activity of CNCTC10/84.

ОРГАНИЗАЦИЯ ДОПОЛНИТЕЛЬНОГО БИОЛОГИЧЕСКОГО ОБРАЗОВАНИЯ В ЛЕТНИХ ОЗДОРОВИТЕЛЬНЫХ ЛАГЕРЯХ

Statement of the problem. The article analyzes the problem of organizing the activities of schoolchildren in the field of additional biological education. The purpose of the article is to prepare and justify the methodological features of the organization of additional biological education in summer health camps. The research methodology consists of normative legal documents in the field of additional education, analysis and synthesis of research works by Russian scientists, advanced and mass experience of biology teachers. Research results. The types and kinds of summer health camps and the duration of children’s stay in them are defined. The structure and direction of activities in the health camp are analyzed and synthesized. The specificity of the content of teachers’ work in the field of ecological and biological orientation of educational camp programs is revealed. Examples of recommended ways to organize specialized health camps of ecological and biological orientation are given. Conclusion. Health camp of ecological and biological orientation contributes to the formation of a socially significant, patriotic position of students, allows them to acquire new knowledge about plants and animals, practical skills of research and project activities, which ultimately implements their creative abilities and develops individual personality qualities.

Twohuman menopausal gonadotrophin (hMG) preparations display different early signaling in vitro.

Commercial hMG drugs are marketed for the treatment of infertility and consist of highly purified hormones acting on receptors expressed in target gonadal cells. Menopur® and Meriofert® are combined preparation of FSH and hCG and are compared in vitro herein. To this purpose, the molecular composition of the two drugs was analyzed by immunoassay. The formation of FSH receptor and LH/hCG receptor (FSHR; LHCGR) heteromer, intracellular Ca2+ and cAMP activation, β-arrestin 2 recruitment and the synthesis of progesterone and estradiol were evaluated in transfected HEK293 and human primary granulosa lutein cells treated by drugs administered within the pg-mg/ml concentration range. Molecular characterization revealed that Meriofert® has a higher FSH:hCG ratio than Menopur® which, in turn, displays the presence of LH molecules. While both drugs induced similar FSHR-LHCGR heteromeric formations and intracellular Ca2+ increase, Meriofert® had a higher potency than Menopur® in inducing a cAMP increase. Moreover, Meriofert® revealed a higher potency than Menopur® in recruiting β-arrestin 2, likely due to different FSH content modulating the tridimensional structure of FSHR-LHCGR-β-arrestin 2 complexes, as evidenced by a decrease in bioluminescence resonance energy transfer signal. This drug-specific activation of intracellular signaling pathways is consistent with the molecular composition of these preparations and impacts downstream progesterone and estradiol production, with Menopur® more potent than Meriofert® in inducing the synthesis of both the steroids. These findings are suggestive of distinct in-vivo activities of these preparations, but require cautious interpretation and further validation from clinical studies.

Effect of Tourist Activities on Fecal and Salivary Glucocorticoids and Immunoglobulin A in Female Captive Asian Elephants in Thailand

Simple SummaryHow tourist camp activities affect individual elephant welfare is an important and highly debated topic. Saliva and fecal samples were collected monthly for 1 year from 44 female Asian elephants that participated in three programs (saddle-, bareback-, or no-riding), and analyzed for glucocorticoids (GC) and immunoglobulin A (IgA). The hypothesis was that better welfare would be associated with low GC and high IgA concentrations. Both biomarkers showed significant variation with respect to camp size, riding activities, tourist-to-elephant ratios and seasonality, but not always consistently between feces and saliva, and not always in the predicted direction. However, there was no clear indication that riding per se negatively affected these two biomarkers. The lack of consistent responses highlights the difficulty in interpreting physiological data in relation to management factors, and suggests more work is needed to differentiate between potential chronic (feces) and acute (saliva) responses.Asian elephants have been an important part of wildlife ecotourism in Thailand for over two decades. Elephants in tourist camps are exposed to a variety of management styles and daily activities that can potentially affect health and welfare. This study investigated relationships between a novel welfare biomarker, immunoglobulin A (IgA), and daily camp activities, and compared results to glucocorticoid (GC) measures. Often no-riding camps are portrayed as providing better welfare than camps that offer riding. Therefore, we predicted that elephants at no-riding camps would have lower GC and higher IgA concentrations, and a low GC/IgA ratio. Forty-four female elephants from six elephant camps were divided into three groups based on riding activities: saddle-riding, bareback-riding, and no-riding. Fecal and salivary samples were collected monthly for 1 year along with evaluations of body condition, foot health, and wounding. Camp environment and management varied among camps, although the major difference was in riding activities. Concentrations of GCs and IgA varied among the working groups, but not always consistently between sample matrices. Overall fecal glucocorticoid metabolite concentrations were lowest in the saddle-riding group. Only in one bareback-riding camp did the elephants exhibit a potentially positive welfare response with a low GC/IgA ratio over time. Other results varied between the two biomarkers, with considerable variability across camps, suggesting there is more to good welfare than whether elephants participate in riding or not. Several other human-induced stressors, like chaining, ankus use, and limited social opportunities are likely to be impacting well-being and should be considered to ensure management practices meet physical and psychological welfare needs.

Teaching Psychiatric Emergencies Using Simulation: an Experience During the Boot Camp.

The purpose of this study is to prepare fourth-year medical students to recognize psychiatric emergencies using simulation technology. The learning experience is accomplished during the boot camp activity designed to train fourth-year medical students in different competencies before transitioning to residency. Ninety-eight fourth-year medical students at Paul L. Foster School of Medicine participated in the boot camp during the 2018-2019 academic year. The participation of the Department of Psychiatry was for a total of four full days divided into 3-h morning and 3-h afternoon sessions with the average of four students per hour per session. The use of high-fidelity simulation and standardized patients to recreate two different clinical scenarios representing acute psychiatric emergencies, followed by structured debriefing, was implemented. Pre- and post-qualitative surveys, which were electronically available via Qualtrics, intended to assess the effectiveness of the curriculum and course teaching modalities during the boot camp. All participants reported improvement on levels of confidence in diagnosis and management of psychiatric emergencies compared with baseline. Overall a statistically significant increase in the Likert score was noted in the post-survey analysis. Teaching psychiatric emergencies utilizing high-fidelity simulation and standardized patient encounters improved student confidence in several competencies. The increase in student confidence can potentially help the learner in transitioning better to residency.

“Germanophilism” of Bishop Dimitri (Abashidze) during the First World War: Bishop’s Answer to “The German Question”

The plot, connected with attacks on the head of the Taurida diocese Dimitri (Abashidze), accused of Germanophilism during the First World War is examined in the article. These events are inscribed in the context of the aggravation of the national question that happened in the wake of the military confrontation between the Russian Empire and Germany. The relevance of this study is due to the insufficient elaboration of the issue of the involvement of the Orthodox clergy in resolving interethnic relations, as well as the participation of the clergy in the Russian nationalist movement. The novelty of the research lies in the introduction of a new corpus of sources into the scientific circulation, which makes it possible to consistently trace how the solution of the regional conflict on ethnic grounds, due to the attention of the capital’s newspapers, reached the state level and was used in the political struggle. It is noted that the appeal of Dimitri (Abashidze) to the priests was the reason for accusing the hierarch of Germanophilism, in which the «Vechernee Vremya» newspaper was most zealous. It is shown that priests and public figures spoke in defense of the bishop. It is proved that the attacks on the Tauride bishop contributed to the intensification of his activities in the right political camp.

DNA damage and growth hormone hypersecretion in pituitary somatotroph adenomas.

Drivers of sporadic benign pituitary adenoma growth are largely unknown. Whole-exome sequencing of 159 prospectively resected pituitary adenomas showed that somatic copy number alteration (SCNA) rather than mutation is a hallmark of hormone-secreting adenomas and that SCNAs correlate with adenoma phenotype. Using single-gene SCNA pathway analysis, we observed that both cAMP and Fanconi anemia DNA damage repair pathways were affected by SCNAs in growth hormone-secreting (GH-secreting) somatotroph adenomas. As somatotroph differentiation and GH secretion are dependent on cAMP activation and we previously showed DNA damage, aneuploidy, and senescence in somatotroph adenomas, we studied links between cAMP signaling and DNA damage. Stimulation of cAMP in C57BL/6 mouse primary pituitary cultures using forskolin or a long-acting GH-releasing hormone (GHRH) analog increased GH production and DNA damage measured by H2AX phosphorylation and a comet assay. Octreotide, a somatostatin receptor ligand that targets somatotroph adenoma GH secretion in patients with acromegaly, inhibited cAMP and GH and reversed DNA damage induction. In vivo long-acting GHRH treatment also induced pituitary DNA damage in mice. We conclude that cAMP, which induces somatotroph proliferation and GH secretion, may concomitantly induce DNA damage, potentially linking hormone hypersecretion to SCNA and genome instability. These results elucidating somatotroph adenoma pathophysiology identify pathways for targeted treatment.

Attenuation effect of polydeoxyribonucleotide on inflammatory cytokines and apoptotic factors induced by particulate matter (PM10) damage in human bronchial cells.

Particulate matter (PM) of 10-μm-sized fine dust in the air penetrates the respiratory tract and contributes to the increasing incidence of various lung diseases, but its definite mechanism is not known. Recently, polydeoxyribonucleotide (PDRN) has been shown to have anti-inflammatory and regenerative effects in various tissues. However, the bronchial-related mechanism is not well-understood. Hence, this experiment is intended to demonstrate the beneficial effect of PDRN administration on PM10-induced injury in human bronchial-derived NCI-H358 cells. To confirm the protective effect of PDRN, PM10 was applied after PDRN pretreatment to confirm changes in NCI-H358 cells. Experiments were conducted to measure cell survival, cytotoxicity, inflammation, and apoptotic factor changes. WST-8 assay was used to confirm cell viability, and lactate dehydrogenase assay was used to obtain cytotoxicity. In addition, changes in inflammatory cytokines and apoptotic factors were confirmed by enzyme-linked immunosorbent assay and Western blot. Decreased cell viability and increased cytotoxicity, inflammatory cytokines, and apoptotic factors were observed after exposure to PM10. However, pretreatment with PDRN enhanced cell viability and reduced cytotoxicity. In addition, the expression of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6 (IL-6), and IL-1β, and cell death factors such as Apaf-1, cyt c, caspase-3, caspase-9, Bid, and Bax/Bcl-2 ratio were decreased by PDRN administration in PM10-exposed NCI-H358 cells. PDRN, an A2AR agonist, affects cAMP activation and regulation of phosphorylation of PKA and CREB. In addition, treatment with A2AR antagonist 3,7-dimethyl-1-propargylxanthine significantly blocked PDRN's effect. These anti-cytotoxicity, anti-inflammation, and anti-apoptosis effects of PDRN can be attributed to the adenosine A2AR enhancing effect on PM10-exposed bronchial cells.

The Role of Epac in Cancer Progression

Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways.

The Ca2+ channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA

The sperm-specific Ca2+ channel CatSper (cation channel of sperm) controls the influx of Ca2+ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activation of PKA is, however, a matter of controversy. To shed light on this question, we used kinetic ion-sensitive fluorometry, patch-clamp recordings, and optochemistry to study transmembrane Ca2+ flux and membrane currents in human sperm from healthy donors and from patients that lack functional CatSper channels. We found that human CatSper is neither activated by intracellular cAMP directly nor indirectly by the cAMP/PKA-signaling pathway. Instead, we show that nonphysiological concentrations of cAMP and membrane-permeable cAMP analogs used to mimic the action of intracellular cAMP activate human CatSper from the outside via a hitherto-unknown extracellular binding site. Finally, we demonstrate that the effects of common PKA inhibitors on human CatSper rest predominantly, if not exclusively, on off-target drug actions on CatSper itself rather than on inhibition of PKA. We conclude that the concept of an intracellular cAMP/PKA-activation of CatSper is primarily based on unspecific effects of chemical probes used to interfere with cAMP signaling. Altogether, our findings solve several controversial issues and reveal a novel ligand-binding site controlling the activity of CatSper, which has important bearings on future studies of cAMP and Ca2+ signaling in sperm.