Center for Physiology and Pharmacology

Austria

Center for Physiology and Pharmacology

Austria

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Bock G.,Institute of Pharmacy | Gebhart M.,Institute of Pharmacy | Scharinger A.,Institute of Pharmacy | Jangsangthong W.,University of Cologne | And 11 more authors.
Journal of Biological Chemistry | Year: 2011

An intramolecular interaction between a distal (DCRD) and a proximal regulatory domain (PCRD) within the C terminus of long Ca v1.3 L-type Ca 2+ channels (Ca v1.3 L) is a major determinant of their voltage- and Ca 2+-dependent gating kinetics. Removal of these regulatory domains by alternative splicing generates Ca v1.3 42A channels that activate at a more negative voltage range and exhibit more pronounced Ca 2+-dependent inactivation. Here we describe the discovery of a novel short splice variant (Ca v1.3 43S) that is expressed at high levels in the brain but not in the heart. It lacks the DCRD but, in contrast to Ca v1.3 42A, still contains PCRD. When expressed together with α2δ1 and β3 subunits in tsA-201 cells, Ca v1.3 43S also activated at more negative voltages like Ca v1.3 42A but Ca 2+-dependent inactivation was less pronounced. Single channel recordings revealed much higher channel open probabilities for both short splice variants as compared with Ca v1.3 L. The presence of the proximal C terminus in Ca v1.3 43Schannels preserved their modulation by distal C terminus-containing Ca v1.3- and Ca v1.2-derived C-terminal peptides. Removal of the C-terminal modulation by alternative splicing also induced a faster decay of Ca 2+ influx during electrical activities mimicking trains of neuronal action potentials. Our findings extend the spectrum of functionally diverse Ca v1.3 L-type channels produced by tissue-specific alternative splicing. This diversity may help to fine tune Ca 2+ channel signaling and, in the case of short variants lacking a functional C-terminal modulation, prevent excessive Ca 2+ accumulation during burst firing in neurons. This may be especially important in neurons that are affected by Ca 2+-induced neurodegenerative processes. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Reisinger S.N.,Center for Physiology and Pharmacology | Kong E.,Center for Physiology and Pharmacology | Khan D.,Center for Physiology and Pharmacology | Schulz S.,Center for Physiology and Pharmacology | And 6 more authors.
Neurobiology of Stress | Year: 2016

Major depressive disorder (MDD) is one of the most debilitating psychiatric diseases, affecting a large percentage of the population worldwide. Currently, the underlying pathomechanisms remain incompletely understood, hampering the development of critically needed alternative therapeutic strategies, which further largely depends on the availability of suitable model systems.Here we used a mouse model of early life stress - a precipitating factor for the development of MDD - featuring infectious stress through maternal immune activation (MIA) by polyinosinic:polycytidilic acid (Poly(I:C)) to examine epigenetic modulations as potential molecular correlates of the alterations in brain structure, function and behavior. We found that in adult female MIA offspring anhedonic behavior was associated with modulations of the global histone acetylation profile in the hippocampus. Morevoer, specific changes at the promoter and in the expression of the serotonin transporter (SERT), critically involved in the etiology of MDD and pharmacological antidepressant treatment were detected. Furthermore, an accompanying reduction in hippocampal levels of histone deacetylase (HDAC) 1 was observed in MIA as compared to control offspring.Based on these results we propose a model in which the long-lasting impact of MIA on depression-like behavior and associated molecular and cellular aberrations in the offspring is brought about by the modulation of epigenetic processes and consequent enduring changes in gene expression. These data provide additional insights into the principles underlying the impact of early infectious stress on the development of MDD and may contribute to the development of new targets for antidepressant therapy. © 2016 The Authors.


PubMed | Center for Physiology and Pharmacology and Medical University of Vienna
Type: | Journal: Neurobiology of stress | Year: 2016

Major depressive disorder (MDD) is one of the most debilitating psychiatric diseases, affecting a large percentage of the population worldwide. Currently, the underlying pathomechanisms remain incompletely understood, hampering the development of critically needed alternative therapeutic strategies, which further largely depends on the availability of suitable model systems. Here we used a mouse model of early life stress - a precipitating factor for the development of MDD - featuring infectious stress through maternal immune activation (MIA) by polyinosinic:polycytidilic acid (Poly(I:C)) to examine epigenetic modulations as potential molecular correlates of the alterations in brain structure, function and behavior. We found that in adult female MIA offspring anhedonic behavior was associated with modulations of the global histone acetylation profile in the hippocampus. Morevoer, specific changes at the promoter and in the expression of the serotonin transporter (SERT), critically involved in the etiology of MDD and pharmacological antidepressant treatment were detected. Furthermore, an accompanying reduction in hippocampal levels of histone deacetylase (HDAC) 1 was observed in MIA as compared to control offspring. Based on these results we propose a model in which the long-lasting impact of MIA on depression-like behavior and associated molecular and cellular aberrations in the offspring is brought about by the modulation of epigenetic processes and consequent enduring changes in gene expression. These data provide additional insights into the principles underlying the impact of early infectious stress on the development of MDD and may contribute to the development of new targets for antidepressant therapy.


PubMed | Center for Physiology and Pharmacology
Type: Comparative Study | Journal: Neuro-Signals | Year: 2012

The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase abundantly expressed in the mammalian brain and highly enriched in neuronal growth cones. Inhibitory and facilitatory activities of FAK on neuronal growth have been reported and its role in neuritic outgrowth remains controversial. Unlike other tyrosine kinases, such as the neurotrophin receptors regulating neuronal growth and plasticity, the relevance of FAK for learning and memory in vivo has not been clearly defined yet. A comprehensive study aimed at determining the role of FAK in neuronal growth, neurotransmitter release and synaptic plasticity in hippocampal neurons and in hippocampus-dependent learning and memory was therefore undertaken using the mouse model. Gain- and loss-of-function experiments indicated that FAK is a critical regulator of hippocampal cell morphology. FAK mediated neurotrophin-induced neuritic outgrowth and FAK inhibition affected both miniature excitatory postsynaptic potentials and activity-dependent hippocampal long-term potentiation prompting us to explore the possible role of FAK in spatial learning and memory in vivo. Our data indicate that FAK has a growth-promoting effect, is importantly involved in the regulation of the synaptic function and mediates in vivo hippocampus-dependent spatial learning and memory.

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