I would like to begin with a question about the above photograph of New York street life that I t... more I would like to begin with a question about the above photograph of New York street life that I took while waiting on a street corner for a friend. Although the question is easy to ask, it is extremely difficult to answer, for it not only places us beyond anthropological knowledge and understanding but beyond the limits of science itself.
Calcium (Ca(2+)) controls progression through the mammalian cell cycle by engaging a diverse rang... more Calcium (Ca(2+)) controls progression through the mammalian cell cycle by engaging a diverse range of molecular pathways. While the essential role of spatio-temporal Ca(2+) signalling in the cell cycle is well established, the precise mechanisms by which it regulates cell cycle entry and progression through G1 are not particularly well understood. Here, high-resolution label-free semi-quantitative nLC-MS/MS analysis has been used to support a highly reproducible unbiased analysis of Ca(2+) influx dependent growth factor induced protein expression early in G1 in human fibroblasts. Using this strategy a panel of 182 proteins whose expression was Ca(2+) dependent were identified. Pathway analysis has indicated that Ca(2+) likely regulates cell proliferation via PI3K/AKT pathway and its downstream target mTOR. In addition to cell proliferation found proteins were involved in the regulation of cell morphology and cellular assembly and organization, the environmental clues, which are known to regulate G1 progression. Reported here data represents one of the most comprehensive proteomic datasets of growth factor and Ca(2+) dependent protein expression in the mammalian cell cycle and provides a rich source of publically available data to support continued investigation of the role of Ca(2+) in G1 progression at both the molecular and systems level. The results of this study provide new insight into Ca(2+) dependent regulation of cell cycle. This manuscript reports first to date global analysis of Ca(2+) regulated protein expression changes early in G1 in non-transformed human fibroblast cell line. It also highlights canonical signalling pathways and biological processes that are regulated by the inhibition of Ca(2+) influx. Importantly, it appears that Ca(2+) may be the factor that links cell division with environmental cues, cell morphology and cellular assembly and organization, on which cell proliferation depends. Hence, the findings presented here provide numerous opportunities for more detailed investigations of the mechanism of Ca(2+) dependent regulation of cell cycle at the molecular and systemic level.
New York Stories aims to research and represent the realms of inner expression that constitute pe... more New York Stories aims to research and represent the realms of inner expression that constitute people's lived experiences of urban space but remain beneath the surface of their public activity. The capacity for a complex inner lifeworld-consisting of inner speech, inchoate trajectories of thought, unarticulated moods, random urges, unsymbolised thinking, imagination, sensation, memory-is a distinctive feature of human experience that mediates many realms of everyday life, action and practice. By placing the problem of interiority directly into the field and turning it into an ethnographic, practice-based question to be addressed in collaboration with informants, New York Stories can be seen as an ethnographic attempt to research and represent the everyday experience of living with HIV/AIDS in New York's Lower East Side by examining the complex trajectories of thinking and being that are played out in public spaces but are not necessarily externalised. keywords Inner dialogue, experimental methods, New York City, HIV/AIDS, collaborative ethnography 'A nthropology Is Philosophy with the People in' (Ingold 1992: 696) in that it explores fundamental questions about the human condition but does so by grounding these in the social, moral and political lives of people around the world. Anthropology is simultaneously a fieldwork science and documentary art (Davis 2000) that carries out practical research in
Lunar and Planetary Science Conference Proceedings, Feb 1, 1975
... (1) Phinney et a!. (1972), Meyer (1972), Dymek et a!. (1974), Dowty et al. (1973), Hiava et a... more ... (1) Phinney et a!. (1972), Meyer (1972), Dymek et a!. (1974), Dowty et al. (1973), Hiava et a!. (1973), Powell et a!. (1973), Steele et al. (1972), Cameron et a!. (1973b), Cameron and Delano (1973), Drake et a!. (1973). (g) Bence and Papike (1972), Gancarz et al. ...
Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in culture... more Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in cultured cerebellar granule cells using digital fluorescence microscopy. The ability of Ok-receptor activation to mobllfse Ca2+ was decreased when [Ca2$ was lowered to 10 u.44 (from 1.8 mM). It was enhanced when [Ca2"Ji was raised using 25 mM external Kt or by N-methyl-o-aspartate (NMDA), which selectively activates a distinct Glu-receptor subtype. The enhancement was dependent on entry of external Ca2+. In contrast, the abillty of ACh receptor activation to mobilise Ca2' was not affected by these condttions. Furthermore, pretreatment with pertussis toxin inhibited Ca2+ mobilisatlon in response to Glu-receptor activation without affecting mobillsatlon in response to ACh. However, activation of both receptors mobilised Ca2+ from a common, thapsigargin-sensltlve pool. We conclude that there are differences in the Ca2+ mobilization pathways for the two receptor systems in cerebellar granule cells. The Ca2+-sensitivity of this Ca2+ mobilizing Glu receptor may have implications for its function in neuronal synaptogenesis and plasticity.
... Vol. 1. Lipin BR (1977) The system Mg2SiO4—Fe2SiO4—CaA12Si2O8—Si02 and the origin of Fra Maur... more ... Vol. 1. Lipin BR (1977) The system Mg2SiO4—Fe2SiO4—CaA12Si2O8—Si02 and the origin of Fra Mauro basalts. ... Rutherford MJ, Hess PC, Ryerson FJ, Campbell HW, and Dick PA (1976) The chemistry, origin and petrogenetic implications of lunar granite and monzonite. Proc. ...
The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocann... more The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocannabinoid system. However, the validity of this categorization is still under debate mainly due to the lack of potent and selective agonists and antagonists of GPR55. Binding assays are not yet available for GPR55 screening and GPR55 signal pathways discrepancies have been reported. In this context, we have designed and synthesized novel GPR55 ligands based on a chromenopyrazole scaffold. Appraisal of GPR55 activity was accomplished by a label-free cell-impedance based assay using GPR55-HEK293. The real-time impedance responses provide an integrative assessment of the cellular consequence to GPR55 stimulation taking into account the different possible signaling pathways. Potent GPR55 partial agonists (14b, 18b, 19b, 20b, and 21-24) have been identified; one of them (14b) being selective vs classical cannabinoid receptors. Upon antagonist treatment, the chromenopyrazoles 21-24 inhibited lysophosphatidylinositol (LPI) effect. One of these GPR55 antagonists (21) is fully selective vs classic cannabinoid receptors. Compared to LPI, predicted physicochemical parameters of the new compounds suggest a clear pharmacokinetic improvement.
To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the ... more To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the cannabinoids. In order to further study the function of GPR55, new potent and selective ligands are needed. In this study, we utilized the screening results from PubChem bioassay AID 1961 which reports the results of Image-based HTS for Selective Agonists of GPR55. Three compounds, CID1792579, CID1252842 and CID1011163, were further evaluated and used as a starting point to create a series of nanomolar potency GPR55 agonists with N-(4-sulfamoylphenyl)thiourea scaffold. The GPR55 activity of the compounds were screened by using a commercial β-arrestin PathHunter assay and the potential compounds were further evaluated by using a recombinant HEK cell line exhibiting GPR55-mediated effects on calcium signalling. The designed compounds were not active when tested against various endocannabinoid targets (CB1R, CB2R, FAAH, MGL, ABHD6 and ABHD12), indicating compounds' selectivity for the GPR55. Finally, structure-activity relationships of these compounds were explored.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investi... more The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investigated in cultured hippocampal cells using Ca(2+) imaging techniques and whole-cell voltage-clamp recording. In neurons, but not glia, global supralinear Ca(2+) release from intracellular stores was observed when the mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was combined with elevated extracellular K(+) levels (10.8 mm), moderate depolarization (15-30 mV), or NMDA (3 micrometer). There was a delay (2-8 min) before the stores were fully charged, and the enhancement persisted for a short period (up to 10 min) after removal of the store-loading stimulus. Studies with the mGlu receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine demonstrated that these effects were mediated by activation of the mGlu(5) receptor subtype. The L-type voltage-gated Ca(2+) channel antagonist nifedipine (10 micrometer) substantially reduced responses to DHPG obtained in the presence of elevate...
Astrocytes possess GPCRs (G-protein-coupled receptors) for neuroactive substances and can respond... more Astrocytes possess GPCRs (G-protein-coupled receptors) for neuroactive substances and can respond via these receptors to signals originating from neurons as well as astrocytes. Like many transmembrane proteins, GPCRs exist in a dynamic equilibrium between receptors expressed at the plasma membrane and those present within intracellular trafficking compartments. The characteristics of GPCR trafficking within astrocytes have not been investigated. We therefore monitored the trafficking of recombinant fluorescent protein chimeras of the CB1R (cannabinoid receptor 1) that is thought to be expressed natively in astrocytes. CB1R chimeras displayed a marked punctate intracellular localization when expressed in cultured rat visual cortex astrocytes, an expression pattern reminiscent of native CB1R expression in these cells. Based upon trafficking characteristics, we found the existence of two populations of vesicular CB1R puncta: (i) relatively immobile puncta with movement characteristic o...
Page 1. Phycologia (2002) Volume 41 (5), 517-522 Published 30 October 2002 Interactive effects of... more Page 1. Phycologia (2002) Volume 41 (5), 517-522 Published 30 October 2002 Interactive effects of sedimentation and microtopography on the abundance of subtidal turf-forming algae ANDREW D. IRVING AND SEAN D. CONNELL * ...
Philosophical Transactions of the Royal Society B: Biological Sciences, 2013
The endocrine hormone leptin plays a key role in regulating food intake and body weight via its a... more The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.
Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pai... more Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pain. We have investigated the location and function of cannabinoid receptors on cultured neonatal dorsal root ganglion (DRG) neurones and F-11 cells, a dorsal root ganglionĂ—neuroblastoma hybridoma which displays several of the features of authentic DRG neurones. CB 1 receptor immunolabelling was observed on the cell bodies and as fine puncta on processes of both cultured DRG neurones and F-11 cells. Additionally, fluorescence-activated cell sorting (FACS) analysis provided evidence that both CB 1 and CB 2 receptors are expressed on populations of cells within the cultured DRG and F-11 cells. The cannabinoid receptor agonist (+)-WIN55212 (10 and 100 nM) inhibited the mean voltage-activated Ca 2+ current in DRG neurones by 21% and 30%, respectively. The isomer, (Ϫ)-WIN55212 (10 and 100 nM) produced significantly less inhibition of 6% and 10% respectively. The CB 1 selective receptor antagonist SR141716A (100 nM) enhanced the peak high voltage-activated Ca 2+ current by 24% and simultaneous application of SR141716A (100 nM) and (+)-WIN55212 (100 nM) resulted in a significant attenuation of the inhibition obtained with (+)-WIN55212 alone. These data give functional evidence for the hypothesis that the analgesic actions of cannabinoids may be mediated by presynaptic inhibition of transmitter release in sensory neurones.
Recent studies have implicated the hormone leptin in synaptic plasticity associated with neuronal... more Recent studies have implicated the hormone leptin in synaptic plasticity associated with neuronal development and learning and memory. Indeed, leptin facilitates hippocampal long-term potentiation and leptin-insensitive rodents display impaired hippocampal synaptic plasticity suggesting a role for endogenous leptin. Structural changes are also thought to underlie activity-dependent synaptic plasticity and this may be regulated by specific growth factors. As leptin is reported to have neurotrophic actions, we have examined the effects of leptin on the morphology and filopodial outgrowth in hippocampal neurons. Here, we demonstrate that leptin rapidly enhances the motility and density of dendritic filopodia and subsequently increases the density of hippocampal synapses. This process is dependent on the synaptic activation of NR2A-containing NMDA receptors and is mediated by the MAPK (ERK) signaling pathway. As dendritic morphogenesis is associated with activity-dependent changes in synaptic strength, the rapid structural remodeling of dendrites by leptin has important implications for its role in regulating hippocampal synaptic plasticity and neuronal development.
1. Understanding the factors that influence habitat persistence is a central theme in ecology, pa... more 1. Understanding the factors that influence habitat persistence is a central theme in ecology, particularly for habitats created by terrestrial and aquatic primary producers that are some of the world's most extensive and ecologically important. 2. Many species have positive (e.g. farming) or negative effects (e.g. herbivory) on the abundance of primary producers, potentially causing wholesale switches in habitat structure if the net outcome of effects moves toward one extreme (e.g. over-grazing). Predicting the conditions under which such switches occur remains a key challenge for ecologists. 3. The purpose of this study was to understand how co-habiting species of opposing effect (damselfish as habitat facilitators vs. sea urchins as habitat consumers) can directly and indirectly influence the persistence of algal habitats on a tropical coast, including their potential to initiate switches among habitat types (productive 'turfs' of filamentous algae vs. 'barrens' of encrusting algae). 4. Using a series of five independent experiments, we observed that damselfish facilitated the production of algal turfs both directly, through active farming of selected species, and indirectly, by vigorously attacking and expelling invading urchins from the local area (i.e. preventing herbivory). In contrast, urchins consumed algal turf to directly maintain barrens. 5. The negative effects of urchins on algal turf were strong enough to initiate a habitat switch from turf to barrens, but this was conditional upon the absence of damselfish and the presence of a particular species of urchin. 6. Synthesis. These results build upon our understanding of the dynamics of habitat persistence by demonstrating the conditions where biological interactions of opposing direction (positive vs. negative) maintain or switch habitat types. Such knowledge is central to addressing global concerns about habitat loss and predicting the occurrence of switches to less-productive states.
Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in culture... more Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in cultured cerebellar granule cells using digital fluorescence microscopy. The ability of Ok-receptor activation to mobllfse Ca2+ was decreased when [Ca2$ was lowered to 10 u.44 (from 1.8 mM). It was enhanced when [Ca2"Ji was raised using 25 mM external Kt or by N-methyl-o-aspartate (NMDA), which selectively activates a distinct Glu-receptor subtype. The enhancement was dependent on entry of external Ca2+. In contrast, the abillty of ACh receptor activation to mobilise Ca2' was not affected by these condttions. Furthermore, pretreatment with pertussis toxin inhibited Ca2+ mobilisatlon in response to Glu-receptor activation without affecting mobillsatlon in response to ACh. However, activation of both receptors mobilised Ca2+ from a common, thapsigargin-sensltlve pool. We conclude that there are differences in the Ca2+ mobilization pathways for the two receptor systems in cerebellar granule cells. The Ca2+-sensitivity of this Ca2+ mobilizing Glu receptor may have implications for its function in neuronal synaptogenesis and plasticity.
Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is... more Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders.
I would like to begin with a question about the above photograph of New York street life that I t... more I would like to begin with a question about the above photograph of New York street life that I took while waiting on a street corner for a friend. Although the question is easy to ask, it is extremely difficult to answer, for it not only places us beyond anthropological knowledge and understanding but beyond the limits of science itself.
Calcium (Ca(2+)) controls progression through the mammalian cell cycle by engaging a diverse rang... more Calcium (Ca(2+)) controls progression through the mammalian cell cycle by engaging a diverse range of molecular pathways. While the essential role of spatio-temporal Ca(2+) signalling in the cell cycle is well established, the precise mechanisms by which it regulates cell cycle entry and progression through G1 are not particularly well understood. Here, high-resolution label-free semi-quantitative nLC-MS/MS analysis has been used to support a highly reproducible unbiased analysis of Ca(2+) influx dependent growth factor induced protein expression early in G1 in human fibroblasts. Using this strategy a panel of 182 proteins whose expression was Ca(2+) dependent were identified. Pathway analysis has indicated that Ca(2+) likely regulates cell proliferation via PI3K/AKT pathway and its downstream target mTOR. In addition to cell proliferation found proteins were involved in the regulation of cell morphology and cellular assembly and organization, the environmental clues, which are known to regulate G1 progression. Reported here data represents one of the most comprehensive proteomic datasets of growth factor and Ca(2+) dependent protein expression in the mammalian cell cycle and provides a rich source of publically available data to support continued investigation of the role of Ca(2+) in G1 progression at both the molecular and systems level. The results of this study provide new insight into Ca(2+) dependent regulation of cell cycle. This manuscript reports first to date global analysis of Ca(2+) regulated protein expression changes early in G1 in non-transformed human fibroblast cell line. It also highlights canonical signalling pathways and biological processes that are regulated by the inhibition of Ca(2+) influx. Importantly, it appears that Ca(2+) may be the factor that links cell division with environmental cues, cell morphology and cellular assembly and organization, on which cell proliferation depends. Hence, the findings presented here provide numerous opportunities for more detailed investigations of the mechanism of Ca(2+) dependent regulation of cell cycle at the molecular and systemic level.
New York Stories aims to research and represent the realms of inner expression that constitute pe... more New York Stories aims to research and represent the realms of inner expression that constitute people's lived experiences of urban space but remain beneath the surface of their public activity. The capacity for a complex inner lifeworld-consisting of inner speech, inchoate trajectories of thought, unarticulated moods, random urges, unsymbolised thinking, imagination, sensation, memory-is a distinctive feature of human experience that mediates many realms of everyday life, action and practice. By placing the problem of interiority directly into the field and turning it into an ethnographic, practice-based question to be addressed in collaboration with informants, New York Stories can be seen as an ethnographic attempt to research and represent the everyday experience of living with HIV/AIDS in New York's Lower East Side by examining the complex trajectories of thinking and being that are played out in public spaces but are not necessarily externalised. keywords Inner dialogue, experimental methods, New York City, HIV/AIDS, collaborative ethnography 'A nthropology Is Philosophy with the People in' (Ingold 1992: 696) in that it explores fundamental questions about the human condition but does so by grounding these in the social, moral and political lives of people around the world. Anthropology is simultaneously a fieldwork science and documentary art (Davis 2000) that carries out practical research in
Lunar and Planetary Science Conference Proceedings, Feb 1, 1975
... (1) Phinney et a!. (1972), Meyer (1972), Dymek et a!. (1974), Dowty et al. (1973), Hiava et a... more ... (1) Phinney et a!. (1972), Meyer (1972), Dymek et a!. (1974), Dowty et al. (1973), Hiava et a!. (1973), Powell et a!. (1973), Steele et al. (1972), Cameron et a!. (1973b), Cameron and Delano (1973), Drake et a!. (1973). (g) Bence and Papike (1972), Gancarz et al. ...
Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in culture... more Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in cultured cerebellar granule cells using digital fluorescence microscopy. The ability of Ok-receptor activation to mobllfse Ca2+ was decreased when [Ca2$ was lowered to 10 u.44 (from 1.8 mM). It was enhanced when [Ca2"Ji was raised using 25 mM external Kt or by N-methyl-o-aspartate (NMDA), which selectively activates a distinct Glu-receptor subtype. The enhancement was dependent on entry of external Ca2+. In contrast, the abillty of ACh receptor activation to mobilise Ca2' was not affected by these condttions. Furthermore, pretreatment with pertussis toxin inhibited Ca2+ mobilisatlon in response to Glu-receptor activation without affecting mobillsatlon in response to ACh. However, activation of both receptors mobilised Ca2+ from a common, thapsigargin-sensltlve pool. We conclude that there are differences in the Ca2+ mobilization pathways for the two receptor systems in cerebellar granule cells. The Ca2+-sensitivity of this Ca2+ mobilizing Glu receptor may have implications for its function in neuronal synaptogenesis and plasticity.
... Vol. 1. Lipin BR (1977) The system Mg2SiO4—Fe2SiO4—CaA12Si2O8—Si02 and the origin of Fra Maur... more ... Vol. 1. Lipin BR (1977) The system Mg2SiO4—Fe2SiO4—CaA12Si2O8—Si02 and the origin of Fra Mauro basalts. ... Rutherford MJ, Hess PC, Ryerson FJ, Campbell HW, and Dick PA (1976) The chemistry, origin and petrogenetic implications of lunar granite and monzonite. Proc. ...
The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocann... more The orphan G protein-coupled receptor GPR55 has been proposed as a novel receptor of the endocannabinoid system. However, the validity of this categorization is still under debate mainly due to the lack of potent and selective agonists and antagonists of GPR55. Binding assays are not yet available for GPR55 screening and GPR55 signal pathways discrepancies have been reported. In this context, we have designed and synthesized novel GPR55 ligands based on a chromenopyrazole scaffold. Appraisal of GPR55 activity was accomplished by a label-free cell-impedance based assay using GPR55-HEK293. The real-time impedance responses provide an integrative assessment of the cellular consequence to GPR55 stimulation taking into account the different possible signaling pathways. Potent GPR55 partial agonists (14b, 18b, 19b, 20b, and 21-24) have been identified; one of them (14b) being selective vs classical cannabinoid receptors. Upon antagonist treatment, the chromenopyrazoles 21-24 inhibited lysophosphatidylinositol (LPI) effect. One of these GPR55 antagonists (21) is fully selective vs classic cannabinoid receptors. Compared to LPI, predicted physicochemical parameters of the new compounds suggest a clear pharmacokinetic improvement.
To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the ... more To date, many known G protein-coupled receptor 55 (GPR55) ligands are those identified among the cannabinoids. In order to further study the function of GPR55, new potent and selective ligands are needed. In this study, we utilized the screening results from PubChem bioassay AID 1961 which reports the results of Image-based HTS for Selective Agonists of GPR55. Three compounds, CID1792579, CID1252842 and CID1011163, were further evaluated and used as a starting point to create a series of nanomolar potency GPR55 agonists with N-(4-sulfamoylphenyl)thiourea scaffold. The GPR55 activity of the compounds were screened by using a commercial β-arrestin PathHunter assay and the potential compounds were further evaluated by using a recombinant HEK cell line exhibiting GPR55-mediated effects on calcium signalling. The designed compounds were not active when tested against various endocannabinoid targets (CB1R, CB2R, FAAH, MGL, ABHD6 and ABHD12), indicating compounds' selectivity for the GPR55. Finally, structure-activity relationships of these compounds were explored.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2000
The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investi... more The role of metabotropic l-glutamate (mGlu) receptors in supralinear Ca(2+) signaling was investigated in cultured hippocampal cells using Ca(2+) imaging techniques and whole-cell voltage-clamp recording. In neurons, but not glia, global supralinear Ca(2+) release from intracellular stores was observed when the mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) was combined with elevated extracellular K(+) levels (10.8 mm), moderate depolarization (15-30 mV), or NMDA (3 micrometer). There was a delay (2-8 min) before the stores were fully charged, and the enhancement persisted for a short period (up to 10 min) after removal of the store-loading stimulus. Studies with the mGlu receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine demonstrated that these effects were mediated by activation of the mGlu(5) receptor subtype. The L-type voltage-gated Ca(2+) channel antagonist nifedipine (10 micrometer) substantially reduced responses to DHPG obtained in the presence of elevate...
Astrocytes possess GPCRs (G-protein-coupled receptors) for neuroactive substances and can respond... more Astrocytes possess GPCRs (G-protein-coupled receptors) for neuroactive substances and can respond via these receptors to signals originating from neurons as well as astrocytes. Like many transmembrane proteins, GPCRs exist in a dynamic equilibrium between receptors expressed at the plasma membrane and those present within intracellular trafficking compartments. The characteristics of GPCR trafficking within astrocytes have not been investigated. We therefore monitored the trafficking of recombinant fluorescent protein chimeras of the CB1R (cannabinoid receptor 1) that is thought to be expressed natively in astrocytes. CB1R chimeras displayed a marked punctate intracellular localization when expressed in cultured rat visual cortex astrocytes, an expression pattern reminiscent of native CB1R expression in these cells. Based upon trafficking characteristics, we found the existence of two populations of vesicular CB1R puncta: (i) relatively immobile puncta with movement characteristic o...
Page 1. Phycologia (2002) Volume 41 (5), 517-522 Published 30 October 2002 Interactive effects of... more Page 1. Phycologia (2002) Volume 41 (5), 517-522 Published 30 October 2002 Interactive effects of sedimentation and microtopography on the abundance of subtidal turf-forming algae ANDREW D. IRVING AND SEAN D. CONNELL * ...
Philosophical Transactions of the Royal Society B: Biological Sciences, 2013
The endocrine hormone leptin plays a key role in regulating food intake and body weight via its a... more The endocrine hormone leptin plays a key role in regulating food intake and body weight via its actions in the hypothalamus. However, leptin receptors are highly expressed in many extra-hypothalamic brain regions and evidence is growing that leptin influences many central processes including cognition. Indeed, recent studies indicate that leptin is a potential cognitive enhancer as it markedly facilitates the cellular events underlying hippocampal-dependent learning and memory, including effects on glutamate receptor trafficking, neuronal morphology and activity-dependent synaptic plasticity. However, the ability of leptin to regulate hippocampal synaptic function markedly declines with age and aberrant leptin function has been linked to neurodegenerative disorders such as Alzheimer's disease (AD). Here, we review the evidence supporting a cognitive enhancing role for the hormone leptin and discuss the therapeutic potential of using leptin-based agents to treat AD.
Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pai... more Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pain. We have investigated the location and function of cannabinoid receptors on cultured neonatal dorsal root ganglion (DRG) neurones and F-11 cells, a dorsal root ganglionĂ—neuroblastoma hybridoma which displays several of the features of authentic DRG neurones. CB 1 receptor immunolabelling was observed on the cell bodies and as fine puncta on processes of both cultured DRG neurones and F-11 cells. Additionally, fluorescence-activated cell sorting (FACS) analysis provided evidence that both CB 1 and CB 2 receptors are expressed on populations of cells within the cultured DRG and F-11 cells. The cannabinoid receptor agonist (+)-WIN55212 (10 and 100 nM) inhibited the mean voltage-activated Ca 2+ current in DRG neurones by 21% and 30%, respectively. The isomer, (Ϫ)-WIN55212 (10 and 100 nM) produced significantly less inhibition of 6% and 10% respectively. The CB 1 selective receptor antagonist SR141716A (100 nM) enhanced the peak high voltage-activated Ca 2+ current by 24% and simultaneous application of SR141716A (100 nM) and (+)-WIN55212 (100 nM) resulted in a significant attenuation of the inhibition obtained with (+)-WIN55212 alone. These data give functional evidence for the hypothesis that the analgesic actions of cannabinoids may be mediated by presynaptic inhibition of transmitter release in sensory neurones.
Recent studies have implicated the hormone leptin in synaptic plasticity associated with neuronal... more Recent studies have implicated the hormone leptin in synaptic plasticity associated with neuronal development and learning and memory. Indeed, leptin facilitates hippocampal long-term potentiation and leptin-insensitive rodents display impaired hippocampal synaptic plasticity suggesting a role for endogenous leptin. Structural changes are also thought to underlie activity-dependent synaptic plasticity and this may be regulated by specific growth factors. As leptin is reported to have neurotrophic actions, we have examined the effects of leptin on the morphology and filopodial outgrowth in hippocampal neurons. Here, we demonstrate that leptin rapidly enhances the motility and density of dendritic filopodia and subsequently increases the density of hippocampal synapses. This process is dependent on the synaptic activation of NR2A-containing NMDA receptors and is mediated by the MAPK (ERK) signaling pathway. As dendritic morphogenesis is associated with activity-dependent changes in synaptic strength, the rapid structural remodeling of dendrites by leptin has important implications for its role in regulating hippocampal synaptic plasticity and neuronal development.
1. Understanding the factors that influence habitat persistence is a central theme in ecology, pa... more 1. Understanding the factors that influence habitat persistence is a central theme in ecology, particularly for habitats created by terrestrial and aquatic primary producers that are some of the world's most extensive and ecologically important. 2. Many species have positive (e.g. farming) or negative effects (e.g. herbivory) on the abundance of primary producers, potentially causing wholesale switches in habitat structure if the net outcome of effects moves toward one extreme (e.g. over-grazing). Predicting the conditions under which such switches occur remains a key challenge for ecologists. 3. The purpose of this study was to understand how co-habiting species of opposing effect (damselfish as habitat facilitators vs. sea urchins as habitat consumers) can directly and indirectly influence the persistence of algal habitats on a tropical coast, including their potential to initiate switches among habitat types (productive 'turfs' of filamentous algae vs. 'barrens' of encrusting algae). 4. Using a series of five independent experiments, we observed that damselfish facilitated the production of algal turfs both directly, through active farming of selected species, and indirectly, by vigorously attacking and expelling invading urchins from the local area (i.e. preventing herbivory). In contrast, urchins consumed algal turf to directly maintain barrens. 5. The negative effects of urchins on algal turf were strong enough to initiate a habitat switch from turf to barrens, but this was conditional upon the absence of damselfish and the presence of a particular species of urchin. 6. Synthesis. These results build upon our understanding of the dynamics of habitat persistence by demonstrating the conditions where biological interactions of opposing direction (positive vs. negative) maintain or switch habitat types. Such knowledge is central to addressing global concerns about habitat loss and predicting the occurrence of switches to less-productive states.
Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in culture... more Ca2+ mobilisation induced by L-glutamate (GM) and acetylcholine (ACh) has been studied in cultured cerebellar granule cells using digital fluorescence microscopy. The ability of Ok-receptor activation to mobllfse Ca2+ was decreased when [Ca2$ was lowered to 10 u.44 (from 1.8 mM). It was enhanced when [Ca2"Ji was raised using 25 mM external Kt or by N-methyl-o-aspartate (NMDA), which selectively activates a distinct Glu-receptor subtype. The enhancement was dependent on entry of external Ca2+. In contrast, the abillty of ACh receptor activation to mobilise Ca2' was not affected by these condttions. Furthermore, pretreatment with pertussis toxin inhibited Ca2+ mobilisatlon in response to Glu-receptor activation without affecting mobillsatlon in response to ACh. However, activation of both receptors mobilised Ca2+ from a common, thapsigargin-sensltlve pool. We conclude that there are differences in the Ca2+ mobilization pathways for the two receptor systems in cerebellar granule cells. The Ca2+-sensitivity of this Ca2+ mobilizing Glu receptor may have implications for its function in neuronal synaptogenesis and plasticity.
Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is... more Growing evidence suggests that pathological overactivation of the endocannabinoid system (ECS) is associated with dyslipidemia, obesity and diabetes. Indeed, this signalling system acting through cannabinoid receptors has been shown to function both centrally and peripherally to regulate feeding behaviour as well as energy expenditure and metabolism. Consequently, modulation of these receptors can promote significant alterations in body weight and associated metabolic profile. Importantly, blocking cannabinoid receptor type 1 function has been found to prevent obesity and metabolic dysfunction in various murine models and in humans. Here we provide a detailed account of the known physiological role of the ECS in energy balance, and explore how recent studies have delivered novel insights into the potential targeting of this system as a therapeutic means for treating obesity and related metabolic disorders.
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Papers by Andrew Irving