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Terry Crow - One of the best experts on this subject based on the ideXlab platform.
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14-3-3 Proteins Interact with the β-Thymosin Repeat Protein
2015Co-Authors: Terry Crow, Juan-juan Xue-bian, Joseph T NearyAbstract:Conditioned stimulus pathway protein 24 (Csp24) is a β-thymosin-like protein that is homologous to other members of the family of β-thymosin repeat proteins that contain multiple actin binding domains. Actin co-precipitates with Csp24 and co-localizes with it in the cytosol of type-B photoreceptor cell bodies. Several signal transduction pathways have been shown to regulate the phosphorylation of Csp24 and contribute to cellular plasticity. Here, we report the identification of the adapter protein 14-3-3 in lysates of the Hermissenda circumesophageal nervous system and its interaction with Csp24. Immunoprecipitation experiments using an antibody that is broadly reactive with several isoforms of the 14-3-3 family of proteins showed that Csp24 co-precipitates with 14-3-3 protein, and nervous systems stimulated with 5-HT exhibited a significant increase in co-precipitated Csp24 probed with a phosphospecific antibody as compared with controls. These results indicate that posttranslational modifications of Csp24 regulate its interaction with 14-3-3 protein, and suggest that this mechanism may contribute to the control of intrinsic enhanced excitability. Keywords actin; β-thymosin repeat proteins; Csp24; 14-3-3 proteins; Hermissenda B-photorecceptors; protei
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POSTER PRESENTATION Network model for visually mediated ciliary
2013Co-Authors: Locomotion In Hermissenda, Douglas A Baxter, Terry CrowAbstract:The overall goal of this study is to investigate the ways in which learning modifies behavior. A combination of computational and empirical studies is being used to address this issue. Empirical studies investigate learning from a cellular and synaptic perspective in the relatively simple nervous system of the nudibranch mollusk Hermissenda [1-3]. Pavlovian conditioning produces light-elicited inhibition of normal positive phototaxis in Hermissenda. Learning changes both cellular excitability and synaptic strength in the neural circuit that supports phototaxis. In the present study, a model of the circuit that supports visually mediated locomotion (Fig. 1A) was developed. Consistent with empirical observations, simulated responses to light increased the level of VP 1 spike activity (Fig. 1B1), which is equivalent to positiv
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statocyst hair cell activation of identified interneurons and foot contraction motor neurons in Hermissenda
Journal of Neurophysiology, 2004Co-Authors: Terry Crow, Lian Ming TianAbstract:Pavlovian conditioning of Hermissenda produces both light-elicited inhibition of normal positive phototactic behavior and conditioned stimulus (CS)-elicited foot-shortening. Rotation, the unconditi...
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Inhibition of conditioned stimulus pathway phosphoprotein 24 expression blocks the development of intermediate-term memory in Hermissenda
The Journal of Neuroscience, 2003Co-Authors: Terry Crow, John B. Redell, Lian Ming Tian, Juan Xue-bian, Pramod K. DashAbstract:Studies of memory consolidation have identified multiple phases or stages in the formation of memories. The multiple components of memory can be broadly divided into the three phases; short-term, intermediate-term, and long-term. Although molecular changes underlying short- and long-term memory have been examined extensively, the molecular mechanisms supporting the formation of intermediate-term memory are poorly understood. In several examples of cellular and synaptic plasticity, intermediate memory depends on translation but not transcription. One-trial conditioning in Hermissenda results in the development of intermediate memory that is associated with enhanced cellular excitability and the phosphorylation of a 24 kDa protein referred to as conditioned stimulus pathway phosphoprotein (Csp24). Using amino acid sequences derived from Csp24 peptide fragments, a full-length cDNA was cloned and shown to contain multiple β-thymosin-like domains. The expression of Csp24 and the development of enhanced excitability, a characteristic of intermediate memory, were blocked by antisense oligonucleotide-mediated downregulation of Csp24 without affecting the induction of immediate enhanced excitability, a characteristic of short-term memory. These results demonstrate that the synthesis of Csp24 is required for the development and maintenance of intermediate memory.
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serotonin activation of the erk pathway in Hermissenda contribution of calcium dependent protein kinase c
Journal of Neurochemistry, 2001Co-Authors: Terry Crow, Juanjuan Xuebian, Vilma Siddiqi, Joseph T NearyAbstract:The mitogen-activated protein kinase (MAPK) cascade is an important contributor to synaptic plasticity and learning in both vertebrates and invertebrates. In the nudibranch mollusk Hermissenda, phosphorylation and activation of the extracellular signal-regulated protein kinase (ERK), a key member of a MAPK cascade, is produced by one-trial and multitrial Pavlovian conditioning. Several signal transduction pathways that are activated by 5-hydroxytryptamine (5-HT) and may contribute to conditioning have been identified in type B photoreceptors. However, the regulation of ERK activity by ‘upstream’ signaling molecules has not been previously investigated in Hermissenda. In the present study we examined the role of protein kinase C (PKC) in the serotonin (5-HT) activation of the ERK pathway. The phorbol ester TPA produced an increase in ERK phosphorylation that was blocked by the PKC inhibitors GF109203X or Go6976. TPA-dependent ERK phosphorylation was also blocked by the MEK1 inhibitors PD098059 or U0126. The increased phosphorylation of ERK by 5-HT was reduced but not blocked by pretreatment with the calcium chelator BAPTA-AM or pretreatment with Go6976 or GF109203X. These results indicate that Ca2+-dependent PKC activation contributes to ERK phosphorylation, although a PKC-independent pathway is also involved in 5-HT-dependent ERK phosphorylation and activation.
Joseph T Neary - One of the best experts on this subject based on the ideXlab platform.
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14-3-3 Proteins Interact with the β-Thymosin Repeat Protein
2015Co-Authors: Terry Crow, Juan-juan Xue-bian, Joseph T NearyAbstract:Conditioned stimulus pathway protein 24 (Csp24) is a β-thymosin-like protein that is homologous to other members of the family of β-thymosin repeat proteins that contain multiple actin binding domains. Actin co-precipitates with Csp24 and co-localizes with it in the cytosol of type-B photoreceptor cell bodies. Several signal transduction pathways have been shown to regulate the phosphorylation of Csp24 and contribute to cellular plasticity. Here, we report the identification of the adapter protein 14-3-3 in lysates of the Hermissenda circumesophageal nervous system and its interaction with Csp24. Immunoprecipitation experiments using an antibody that is broadly reactive with several isoforms of the 14-3-3 family of proteins showed that Csp24 co-precipitates with 14-3-3 protein, and nervous systems stimulated with 5-HT exhibited a significant increase in co-precipitated Csp24 probed with a phosphospecific antibody as compared with controls. These results indicate that posttranslational modifications of Csp24 regulate its interaction with 14-3-3 protein, and suggest that this mechanism may contribute to the control of intrinsic enhanced excitability. Keywords actin; β-thymosin repeat proteins; Csp24; 14-3-3 proteins; Hermissenda B-photorecceptors; protei
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serotonin activation of the erk pathway in Hermissenda contribution of calcium dependent protein kinase c
Journal of Neurochemistry, 2001Co-Authors: Terry Crow, Juanjuan Xuebian, Vilma Siddiqi, Joseph T NearyAbstract:The mitogen-activated protein kinase (MAPK) cascade is an important contributor to synaptic plasticity and learning in both vertebrates and invertebrates. In the nudibranch mollusk Hermissenda, phosphorylation and activation of the extracellular signal-regulated protein kinase (ERK), a key member of a MAPK cascade, is produced by one-trial and multitrial Pavlovian conditioning. Several signal transduction pathways that are activated by 5-hydroxytryptamine (5-HT) and may contribute to conditioning have been identified in type B photoreceptors. However, the regulation of ERK activity by ‘upstream’ signaling molecules has not been previously investigated in Hermissenda. In the present study we examined the role of protein kinase C (PKC) in the serotonin (5-HT) activation of the ERK pathway. The phorbol ester TPA produced an increase in ERK phosphorylation that was blocked by the PKC inhibitors GF109203X or Go6976. TPA-dependent ERK phosphorylation was also blocked by the MEK1 inhibitors PD098059 or U0126. The increased phosphorylation of ERK by 5-HT was reduced but not blocked by pretreatment with the calcium chelator BAPTA-AM or pretreatment with Go6976 or GF109203X. These results indicate that Ca2+-dependent PKC activation contributes to ERK phosphorylation, although a PKC-independent pathway is also involved in 5-HT-dependent ERK phosphorylation and activation.
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phosphorylation of mitogen activated protein kinase by one trial and multi trial classical conditioning
The Journal of Neuroscience, 1998Co-Authors: Terry Crow, Juanjuan Xuebian, Vilma Siddiqi, Yuan Kang, Joseph T NearyAbstract:The pathway supporting the conditioned stimulus (CS) is one site of plasticity that has been studied extensively in conditioned Hermissenda . Several signal transduction pathways have been implicated in classical conditioning of this preparation, although the major emphasis has been on protein kinase C. Here we provide evidence for the activation and phosphorylation of a mitogen-activated protein kinase (MAPK) pathway by one-trial and multi-trial conditioning. A one-trial in vitro conditioning procedure consisting of light (CS) paired with the application of 5-HT results in the increased incorporation of 32PO4into proteins detected with two-dimensional gel electrophoresis. Two of the phosphoproteins have molecular weights of 44 and 42 kDa, consistent with extracellular signal-regulated protein kinases (ERK1 and ERK2). Phosphorylation of the 44 and 42 kDa proteins by one-trial conditioning was inhibited by pretreatment with PD098059, A MEK1 (ERK-Activating kinase) inhibitor. Assays of ERK activity with brain myelin basic protein as a substrate revealed greater ERK activity for the group that received one-trial conditioning compared with an unpaired control group. Western blot analysis of phosphorylated ERK using antibodies recognizing the dually phosphorylated forms of ERK1 and ERK2 showed an increase in phosphorylation after one-trial conditioning compared with unpaired controls. The increased phosphorylation of ERK after one-trial conditioning was blocked by pretreatment with PD098059. Hermissenda that received 10 or 15 conditioning trials showed significant behavioral suppression compared with pseudo-random controls. After conditioning and behavioral testing, the conditioned animals showed significantly greater phosphorylation of ERK compared with the pseudo-random controls. These results show that the ERK–MAPK signaling pathway is activated in Pavlovian conditioning of Hermissenda .
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Phosphorylation of mitogen-activated protein kinase by one-trial and multi-trial classical conditioning. J Neurosci 18:3480–3487
1998Co-Authors: Terry Crow, Vilma Siddiqi, Yuan Kang, Juan-juan Xue-bian, Joseph T NearyAbstract:The pathway supporting the conditioned stimulus (CS) is one site of plasticity that has been studied extensively in conditioned Hermissenda. Several signal transduction pathways have been implicated in classical conditioning of this preparation, although the major emphasis has been on protein kinase C. Here we provide evidence for the activation and phosphorylation of a mitogen-activated protein kinase (MAPK) pathway by one-trial and multi-trial conditioning. A one-trial in vitro conditioning procedure consisting of light (CS) paired with the application of 5-HT results in the increased incorporation of 32 PO4 into proteins detected with two-dimensional gel electrophoresis. Two of the phosphoproteins have molecular weights of 44 and 42 kDa, consistent with extracellular signal-regulated protein kinases (ERK1 and ERK2). Phosphorylation of the 4
Daniel L Alkon - One of the best experts on this subject based on the ideXlab platform.
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Neural Correlates of Associative Training in Hermissenda
2013Co-Authors: Daniel L AlkonAbstract:ABSTRACT Hair cells in Hermissenda respond to illumination of the ipsilateral and contralateral eyes. These responses are modified by associative training of the animal. The observed electrophysiological changes appear to result from changes in the photoreceptors ' synaptic input to the hair cells
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Interaction of Chemosensory, Visual, and Statocyst Pathways in Hermissenda crassicornis
2013Co-Authors: Daniel L Alkon, Tadashi Akaike, June HarriganAbstract:the eye, optic ganglion cells, and statocyst hair cells of the nudibranch mollusk Hermissenda crassicornis responded in specific ways, as recorded intracellularly, to stimulation of the chemosensory pathway originating at the tentacular chemoreceptors as well as to stimulation of the visual pathway originating at the photoreceptors. Synaptic inhibition of photoreceptors occurs via the chemosensory pathway. The possible significance of such intersensory interaction is discussed with reference to preliminary investigation of the animal's gustatory behavior and possible neural mechanisms of behavioral choice
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Intersensory Interactions in Hermissenda
2013Co-Authors: Daniel L AlkonAbstract:ABSTRACT Hair cells of the Hermissenda statocyst respond to photic stimulation. This response requires the presence of at least one of the two eyes. Two principal hair cell responses to light were observed. The activity of photoreceptors in response to a light step is interrupted during firing of contralateral hair cells. The intersensory interactions between the statocyst and visual pathway underlying these responses were examined with simultaneous intracellular recordings. Evidence is presented that the statocyst of Hermissenda is an important channel for visual information
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Hair Cell Interactions in the Statocyst of
2008Co-Authors: Peter B. Detwiler, Daniel L AlkonAbstract:ABSTRACT Hair cells in the statocyst of Hermissenda crassicornis respond to mechanical stimulation with a short latency (<2 ms) depolarizing generator potential that is followed by hyperpolarization and inhibition of spike activity. Mechanically evoked hyperpolarization and spike inhibition were abolished by cutting the static nerve, repetitive mechanical stimulation, tetrodotoxin (TTX), and Co++. Since none of these procedures markedly altered the generator potential it was concluded that the hyperpolarization is an inhibitory synaptic potential and not a component of the mechanotransduction process. Intracellular recordings from pairs of hair cells in the same statocyst and in statocysts on opposite sides of the brain revealed that hair cells are connected by chemical and/or electrical synapses. All chemical interactions were inhibitory. Hyperpolarization and spike inhibition result from inhibitory interactions between hair cells in the same and in opposite statocysts
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Classical conditioning and protein kinase C activation regulate the same single potassium channel in Hermissenda crassicornis photoreceptors.
Proceedings of the National Academy of Sciences of the United States of America, 1992Co-Authors: Rene Etcheberrigaray, I. Izja Lederhendler, Louis D. Matzel, Daniel L AlkonAbstract:The patch-clamp technique was used to study the effects of classical conditioning and protein kinase C (PKC) activation on K+ channels of identified neurons in the snail Hermissenda crassicornis. Here we present evidence that classical conditioning and PKC activation similarly modify the same K+ channel. K+ channels were recorded in cells from animals with different training experience. The 64-pS K+ channel appeared with significantly lower frequency in the conditioned group compared to the frequencies in control animals (naive and unpaired). In addition, when present, the 64-pS channel exhibited a lower percentage of open time and an increased interval between opening bursts in cells from conditioned animals. The 42-pS K+ channel was observed with about the same frequency in all three groups, and its percentage of open time was invariant, regardless of the animal's experience. Incubation of the photoreceptor with the PKC activator phorbol 12,13-dibutyrate (PDBu) led to a profound decrease in the percentage of open time of the 64-pS K+ channel, from 35.7% in the control group to 2.5% in the PDBu-treated group. The inactive phorbol 4 alpha-phorbol 12-myristate 13-acetate had no effect. The use of the PKC inhibitor H-7 significantly blocked the phorbol effect. Inside-out patches obtained from phorbol preincubated cells likewise showed the same effect of PDBu on K+ channels, but the effect was not observed when phorbol was added after the cell-free patches were obtained from nontreated cells. By contrast, the percentage of open time of the 42-pS K+ channel remained unchanged after phorbol treatment.
Alan M. Kuzirian - One of the best experts on this subject based on the ideXlab platform.
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contraction of neuronal branching volume an anatomic correlate of pavlovian conditioning associative memory morphologic correlates Hermissenda learning
2016Co-Authors: D L Alkon, I. Izja Lederhendler, Alan M. Kuzirian, Louis D. Matzel, James L. Olds, H. Ikeno, J. Dworkin, Donna L. Mcphie, Bernard G. Schreurs, Carlos CollinAbstract:Associative memory of the mollusc Hermis- senda crassicornis, previously correlated with changes of spe- cific K+ currents, protein phosphorylation, and increased synthesis of mRNA and specific proteins, is here shown to be accompanied by macroscopic alteration in the structure of a single identified neuron, the medial type B photoreceptor cell. Four to five days after training, terminal arborizations of B cells iontophoretically injected with Ni2+ ions and then treated with rubeanic acid were measured with charge-coupled device (CCD)-digitized pseudocolor images of optical sections under "blind" conditions. Boundary volumes enclosing medial-type B-cell arborizations from classically conditioned animals were unequivocally reduced compared with volumes for naive ani- mals or those trained with unpaired stimuli. Branch volume magnitude was correlated with input resistance of the medial type B-cell soma. Such associative learning-induced structural changes may share function with "synapse elimination" de- scribed in developmental contexts.
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memory consolidation in Hermissenda crassicornis
The Biological Bulletin, 2000Co-Authors: D A Epstein, Herman T Epstein, F M Child, Alan M. KuzirianAbstract:Experiments with shell-less molluscs (Aplysia and Hermissenda) have revealed a number of processes that underlie learning by these organisms and also by some vertebrates. Hermissenda, for example, shows significant Pavlovian conditioning capabilities (1). Follow-up investigations on these molluscs dealt with the sensory stimuli needed for short-term memory (STM) and long-term memory (LTM) (2). The relationship of the two memories with in vitro changes in excitatory post-synaptic potentials (EPSPs) have also been investigated in the neural networks of these organisms (3). Many studies of the molecular aspects of these two different memory regimes have led to quite detailed descriptions of the events (4, 5, 6). Both Aplysia and Hermissenda have been tested for their recall of induced behavioral modifications after one, two, or many conditioning events (CEs). In Aplysia, the EPSP component of learning produced by 1 CE was compared to that produced by 5 CEs (3). In Hermissenda, the comparison was made between 2 CEs and 9 CEs (2). Five to ten minutes after finishing one or two conditioning events, both animals exhibited significant behavioral recall (i.e. STM); but there was no recall after an hour or more (i.e. no LTM). The larger numbers of CEs, however, did induce LTM in both species. Since STM and LTM are clearly responding to a different set of conditions, we focused first on what might inhibit or block STM. This problem was partially anticipated in 1900, according to McGaugh (7) who cited Muller and Pilzecker as having found that "memory of newly learned information was disrupted by the learning of other information shortly after the original learning" (8). This concept led us to test, in Hermissenda, whether STM recall (at 5 min) might be blocked simply by the input of additional information (i.e. extraneous sensory stimuli) if the latter were applied within the first 5 min after conditioning. The initial results of the blocking experiments, which showed that the simple sensory inputs blocking STM also blocked LTM, then led to the hypothesis that temporal consolidation of LTM could be detected by measuring when the blocking sensory input was no longer effective. Hermissenda (Sea Life Supply, Sand City, CA) were tested with 2 and 9 paired CEs for induction of STM and LTM. Conditioning events consisted of exposing the animals to 6 s of bright, white light (CS) explicitly paired with 4 s of strong orbital agitation (US) following a 2-s onset delay with an inter-trial interval of 1 min. Recall of the behavioral modification induced by associative conditioning was assessed by recording the animal's change in foot length when presented with 6 s of light alone. The conditioned response (CR) was foot contraction, the unconditioned response (UR) was foot elongation (9). Two paired conditioning events initiated behavioral recall after 5 min but not after 90 min; the LTM input of 9 pairings was recalled at both 5 and 90 min (Fig. 1A). The small and non-overlapping S.E.Ms for each point indicate statistical significance (P = <0.01, t = 3.18). After giving the animals the paired CS and US stimuli leading to STM, we tested two simple paradigms of blocking sensory stimuli. The first was a modification of the conditioning stimuli: dim orange light and very slow orbital rotation. The second blocking stimulus tested consisted of rotating the tray containing the animals upside down and, after 5 s, rotating it upright again (rotational block). Both experimental paradigms blocked STM and LTM (Fig. 1B). To determine the temporal specificity of LTM in Hermissenda, the following experiments were done. Animals were trained with 9 CEs, and the CR was measured at the usual 90 min. However, at selected time intervals (2, 25, 50, 55, 60, 65 min) post-conditioning, the animals were rotationally blocked. Control animals received only the 9 paired CEs. When the animals' behavior was plotted, a clear and decisive LTM consolidation interval in Hermissenda appeared; consolidation occurred between 55 and 60 min (Fig. 1C). Presentations of rotational blocking prior to 55 min totally blocked memory consolidation. However, the stimulus given after 60 had no blocking effects, and the animals demonstrated the CR. The consistency of and surprisingly little variability in the response among the majority of the animals indicated the robustness of the paradigm. When the data were analyzed with t-test and F-test statistics, they were found to be highly significant, whether compared between data points or to zero (P = <0.001, t = 15.24; F-value, inf). 182
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Feeding behavior and growth of Hermissenda crassicornis (Mollusca: Nudibranchia) in the laboratory
Marine and Freshwater Behaviour and Physiology, 1998Co-Authors: Conxita Avila, E Tyndale, Alan M. KuzirianAbstract:The feeding behavior and growth of the nudibranch mollusc Hermissenda crassicomis, a gener‐alist carnivore, has been studied; this species is widely used as a biomedical and neurobiological model. Relative to the stalks, polyps of the hydroid prey, Tubularia crocea, were preferentially consumed by adults of H. crassicomis at a fast rate. Starved slugs did not distinguish between reproductive and unreproductive polyps, but unstarved slugs did select unreproductive polyps of T. ‘crocea. Experiments with diets based on different parts of T. crocea (polyps, stalks, or whole) showed no obvious differences in juvenile growth among treatments, but survival of juveniles was low. Juveniles of H. crassicomis .grew better on a diet of the small anemone Haliplanella luciae than on T. crocea or the anemone Metridium senile. The relationship between body length and wet weight of H. crassicomis was similar for animals grown in the laboratory on a T. crocea diet and specimens from the field.Peer reviewe
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feeding behavior and growth of Hermissenda crassicornis mollusca nudibranchia in the laboratory
Marine and Freshwater Behaviour and Physiology, 1998Co-Authors: Conxita Avila, E Tyndale, Alan M. KuzirianAbstract:The feeding behavior and growth of the nudibranch mollusc Hermissenda crassicomis, a gener‐alist carnivore, has been studied; this species is widely used as a biomedical and neurobiological model. Relative to the stalks, polyps of the hydroid prey, Tubularia crocea, were preferentially consumed by adults of H. crassicomis at a fast rate. Starved slugs did not distinguish between reproductive and unreproductive polyps, but unstarved slugs did select unreproductive polyps of T. ‘crocea. Experiments with diets based on different parts of T. crocea (polyps, stalks, or whole) showed no obvious differences in juvenile growth among treatments, but survival of juveniles was low. Juveniles of H. crassicomis .grew better on a diet of the small anemone Haliplanella luciae than on T. crocea or the anemone Metridium senile. The relationship between body length and wet weight of H. crassicomis was similar for animals grown in the laboratory on a T. crocea diet and specimens from the field.
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induction of metamorphosis in Hermissenda crassicornis larvae molluscs nudibranchia by gaba choline and serotonin
Invertebrate Reproduction & Development, 1996Co-Authors: Conxita Avila, Catherme T Tamse, Alan M. KuzirianAbstract:Summary The nudibranch mollusc Hermissenda crassicornis is currently used as a biomedical model in neurobiological studies. It possesses planktotrophic larvae which metamorphose in the laboratory in the presence of the hydroid Tubularia crocea in yields of about 2–5% (Tamse et al., 1990). This study presents evidence that artificial metamorphic inducers such as GABA (γ-aminobutyric acid), choline, and serotonin (alone or combined with the natural inducer T. crocea), can be used to improve the metamorphic success in H. crassicornis larvae. GABA at 10−5M and 10−4M, choline at 10−3M and 10−4M, and serotonin at 10−5 M and 10−4M, were most effective, while serotonin at 10−3 M was toxic. Larvae 47 and 63 days old metamorphosed at different rates when exposed to the same concentrations of chemicals, but these had no positive effect on young larvae, i.e., 28 and 39 days old. On the other hand, when young larvae were exposed to the natural inducer, an habituation phenomenon was observed, i.e., the larvae did not m...
Victor I. Tsetlin - One of the best experts on this subject based on the ideXlab platform.
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Natural compounds interacting with nicotinic acetylcholine receptors: from low-molecular weight ones to peptides and proteins.
Toxins, 2015Co-Authors: Denis S. Kudryavtsev, Igor E. Kasheverov, Irina V. Shelukhina, Tatyana N. Makarieva, Valentin A. Stonik, Catherine A. Vulfius, Maxim N. Zhmak, Igor Ivanov, Yuri N. Utkin, Victor I. TsetlinAbstract:Nicotinic acetylcholine receptors (nAChRs) fulfill a variety of functions making identification and analysis of nAChR subtypes a challenging task. Traditional instruments for nAChR research are d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various new compounds of different structural classes also interacting with nAChRs have been recently identified. Among the low-molecular weight compounds are alkaloids pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR. To get more selective α-conotoxins, computer modeling of their complexes with acetylcholine-binding proteins and distinct nAChRs was used. Several novel three-finger neurotoxins targeting nAChRs were described and α-Bgt inhibition of GABA-A receptors was discovered. Information on the mechanisms of nAChR interactions with the three-finger proteins of the Ly6 family was found. Snake venom phospholipases A2 were recently found to inhibit different nAChR subtypes. Blocking of nAChRs in Lymnaea stagnalis neurons was shown for venom C-type lectin-like proteins, appearing to be the largest molecules capable to interact with the receptor. A huge nAChR molecule sensible to conformational rearrangements accommodates diverse binding sites recognizable by structurally very different compounds.
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6-Bromohypaphorine from Marine Nudibranch Mollusk Hermissenda crassicornis is an Agonist of Human α7 Nicotinic Acetylcholine Receptor
Marine drugs, 2015Co-Authors: Igor E. Kasheverov, Irina V. Shelukhina, Denis S. Kudryavtsev, Tatyana N. Makarieva, Ekaterina N. Spirova, Alla G. Guzii, Valentin A. Stonik, Victor I. TsetlinAbstract:6-Bromohypaphorine (6-BHP) has been isolated from the marine sponges Pachymatisma johnstoni, Aplysina sp., and the tunicate Aplidium conicum, but data on its biological activity were not available. For the nudibranch mollusk Hermissenda crassicornis no endogenous compounds were known, and here we describe the isolation of 6-BHP from this mollusk and its effects on different nicotinic acetylcholine receptors (nAChR). Two-electrode voltage-clamp experiments on the chimeric α7 nAChR (built of chicken α7 ligand-binding and glycine receptor transmembrane domains) or on rat α4β2 nAChR expressed in Xenopus oocytes revealed no action of 6-BHP. However, in radioligand analysis, 6-BHP competed with radioiodinated α-bungarotoxin for binding to human α7 nAChR expressed in GH4C1 cells (IC50 23 ± 1 μM), but showed no competition on muscle-type nAChR from Torpedo californica. In Ca2+-imaging experiments on the human α7 nAChR expressed in the Neuro2a cells, 6-BHP in the presence of PNU120596 behaved as an agonist (EC50 ~80 μM). To the best of our knowledge, 6-BHP is the first low-molecular weight compound from marine source which is an agonist of the nAChR subtype. This may have physiological importance because H. crassicornis, with its simple and tractable nervous system, is a convenient model system for studying the learning and memory processes.