Atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves o... more Atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. However, the genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. We have identified a Shox2-Nkx2-5 antagonistic mechanism that primes the pacemaking cell fate in the PV myocardium and SAN in the embryonic stage. Specifically, Shox2 deletion in the Nkx2-5+ domain of the SAN caused sick sinus syndrome, associated with the loss of pacemaker program. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. Shox2 interacts with Nkx2-5 directly, and a substantial genome wide co-occupan...
ABSTRACTThalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalam... more ABSTRACTThalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalamus to the cortex. In response to different physiological states and demands TCNs can fire in tonic and/or phasic burst modes. These firing properties of TCNs are supported by precisely timed inhibitory synaptic inputs from the thalamic reticular nucleus and intrinsic currents, including T-type Ca2+ and HCN currents. These intrinsic currents are mediated by Cav3.1 and HCN channel subunits, and alterations in expression or modulation of these channels can have dramatic implications on thalamus function. The factors that regulate these currents controlling the firing patterns important for integration of the sensory stimuli and the consequences resulting from the disruption of these firing patterns are not well understood. Shox2 is a transcription factor known to be important for pacemaker activity in the heart. We show here that Shox2 is also expressed in adult mouse thalamus. We hypothesi...
Boudaba, Cherif, Laura A. Schrader, and Jeffrey G. Tasker. Physiological evidence for local excit... more Boudaba, Cherif, Laura A. Schrader, and Jeffrey G. Tasker. Physiological evidence for local excitatory synaptic circuits in the rat hypothalamus. J. Neurophysiol. 77: 3396–3400, 1997. We conducted whole cell voltage-clamp and current-clamp recordings in slices of rat hypothalamus to test for local excitatory synaptic circuits. Local excitatory inputs to neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were studied with the use of electrical and chemical stimulation. Extracellular electrical stimulation provided indirect evidence of local excitatory circuits. Single stimuli evoked multiple excitatory postsynaptic potentials (EPSPs) or excitatory postsynaptic currents (EPSCs) in some PVN and SON cells, invoking polysynaptic excitatory inputs. Repetitive stimulation (10–20 Hz, 2–10 s) elicited long afterdischarges of EPSPs/EPSCs, suggesting a potentiation of upstream synapses in a polysynaptic circuit. Bath application of metabotropic glutamate receptor agonist...
The multiple memory systems hypothesis proposes that different types of learning strategies are m... more The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC) and the other group was pre-exposed to a different context (PDC). Our results show that the PTC condition biased mice to place strategy use in males, but this bias was dependent on the presence of ovarian hormones in females.
ABSTRACT The question how neuronal systems process sensory information is as crucial for neurosci... more ABSTRACT The question how neuronal systems process sensory information is as crucial for neuroscience as it is for bio-inspired technical applications. Classification of multidimensional data is a common problem in signal and data analysis. The architecture of the olfactory system maps particularly well onto this problem [1]. Here, we present an olfaction-inspired spiking classifier network that achieves the performance of a Naive Bayes classifier on a benchmark data set, and demonstrate its ability to solve nonlinear classification problems. Moreover, we show an implementation of this network on a neuromorphic hardware system comprising 192 spiking analog hardware neurons embedded in digital control circuitry. Neuronal computations in this system operate at a speedup factor of 10^4 compared to biological real time, enabling high-thoughput neurocomputing. The neuromorphic implementation is subject to inherent device mismatch affecting analog components, e.g. neuron parameters, which leads to a decrease of classification performance. As a solution we present an algorithm for self-calibration that takes into account the specific architecture of our network in order to maximally exploit the capabilities of the hardware system. With this algorithm we were able to increase classifier performance on the hardware to a level comparable with a Naive Bayes classifier. As neuronal variation is not only a feature of neuromorphic hardware but also a hallmark of neurons in biological systems, our results provide insight into the biological relevance of neural coding hypotheses thought to operate on a neuronal substrate with heterogeneous sensitivity. References [1] Schmuker, M., and Schneider, G. (2007). Processing and classification of chemical data inspired by insect olfaction. Proc Natl Acad Sci U S A 104, 20285-20289.
American Journal of Physiology-Cell Physiology, 2005
Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the... more Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the nervous system, and it also contributes to the transient outward currents of cardiac myocytes. A-type currents in the dendrites of hippocampal CA1 pyramidal neurons are regulated by activation of ERK/MAPK, and Kv4.2 is the likely pore-forming subunit of that current. We showed previously that Kv4.2 is directly phosphorylated at three sites by ERK/MAPK (T602, T607, and S616). In this study we determined whether direct phosphorylation of Kv4.2 by ERK/MAPK is responsible for the regulation of the A-type current observed in neurons. We made site-directed mutants, changing the phosphosite serine (S) or threonine (T) to aspartate (D) to mimic phosphorylation. We found that the T607D mutation mimicked the electrophysiological changes elicited by ERK/MAPK activation in neurons: a rightward shift of the activation curve and an overall reduction in current compared with wild type (WT). Surprising...
Transient outward K+ currents are particularly important for the regulation of membrane excitabil... more Transient outward K+ currents are particularly important for the regulation of membrane excitability of neurons and repolarization of action potentials in cardiac myocytes. These currents are modulated by PKC (protein kinase C) activation, and the K+- channel subunit Kv4.2 is a major contributor to these currents. Furthermore, the current recorded from Kv4.2 channels expressed in oocytes is reduced by PKC activation. The mechanism underlying PKC regulation of Kv4.2 currents is unknown. In the present study, we determined that PKC directly phosphorylates the Kv4.2 channel protein. In vitro phosphorylation of the intracellular N- and C-termini of Kv4.2 GST (glutathione transferase) tagged fusion protein revealed that the C-terminal of Kv4.2 was phosphorylated by PKC, whereas the N-terminal was not. Amino acid mapping and site-directed mutagenesis revealed that the phosphorylated residues on the Kv4.2 C-terminal were Ser447 and Ser537. A phospho-site-specific antibody showed that phosp...
Spatial memory processing requires functional interaction between the hippocampus and the medial ... more Spatial memory processing requires functional interaction between the hippocampus and the medial entorhinal cortex (MEC). The grid cells of the MEC are most abundant in layer II and rely on a complex network of local inhibitory interneurons to generate spatial firing properties. Stress can cause spatial memory deficits in males, but the specific underlying mechanisms affecting the known memory pathways remain unclear. Stress activates both the autonomic nervous system and the hypothalamic-pituitary-adrenal axis to release norepinephrine (NE) and glucocorticoids, respectively. Given that adrenergic receptor (AR) and glucocorticoid receptor (GR) expression is abundant in the MEC, both glucocorticoids and NE released in response to stress may have rapid effects on MEC-LII networks. We used whole-cell patch clamp electrophysiology in MEC slice preparations from male mice to test the effects of NE and glucocorticoids on inhibitory synaptic inputs of MEC-LII principal cells. Application o...
Post-traumatic stress disorder (PTSD) is characterized by memory disturbances following trauma. A... more Post-traumatic stress disorder (PTSD) is characterized by memory disturbances following trauma. Acute predator threat has emerged as an ethological model of PTSD, yet the effects of predator odor on signaling cascades associated with long-term memory remain poorly understood. In this study, we exposed male and female Wistar rats to the synthetic predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to assess behavioral and physiological responses as well as rapid modulation of signal transduction cascades associated with learning and memory in the male and female hippocampus. During exposure to TMT in the homecage, both male and female animals displayed robust immobility, avoidance, and altered activity as a function of time. Physiologically, TMT exposure increased circulating corticosterone and blood glucose in both male and female rodents, suggesting that TMT evokes sex-independent behavioral and physiological responses. With respect to signal transduction, TMT exposure rapidly reduced phosphorylation of cyclic-adenosine monophosphate response element binding protein (CREB) in the male, but not the female hippocampus. Furthermore, TMT exposure reduced phosphorylation of extracellular signal-regulated kinase 1/2 and increased nuclear expression of the synapto-nuclear messenger protein Jacob in the male hippocampus, consistent with activation of the CREB shut-off pathway. In a follow-up behavioral experiment, post-training exposure to TMT did not affect spatial water maze performance of male rats. However, male rats re-introduced to the context in which TMT had previously been presented displayed avoidance and hyperactivity, but not freezing behavior or elevated corticosterone responses, suggesting that TMT exposure supports a form of contextual conditioning which is not characterized by immobility. Taken together, our findings suggest that TMT evokes similar behavioral and physiological responses in male and female Wistar rats, but affects distinct signaling cascades in the male and female hippocampus which may contribute to behavioral disruptions associated with predator exposure.
Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal n... more Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks for proper brain function. Disruption of this balance during development may lead to autism spectral disorders and epilepsy. Synaptic excitation is counter-balanced by synaptic inhibition but also by regulation attenuation of cell-intrinsic neuronal excitability. To maintain proper excitation levels during development, neurons must sense activity over time and regulate the expression of genes that control these parameters. While this is a critical process, little is known about the transcription factors involved in coordinating gene expression to control excitatory/inhibitory (E/I) synaptic balance. We show here that the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both, in vitro and in vivo as shown by ex vivo analysis of a NeuroD2 KO mouse. Using micro...
This project investigates the role of gonadal hormones in the regulation of Pavlovian fear condit... more This project investigates the role of gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve as an animal model for the development of pathological fear in humans that suffer posttraumatic stress disorders and other anxiety disorders. Despite the increased incidence of PTSD and depressive disorders in women, the specific neurobiological mechanisms of gender differences of PTSD are poorly understood and very little basic research currently investigates this dichotomy. One possible hypothesis is that female hormones also play a role in predisposition to PTSD through epigenetic mechanisms. This concept is currently being tested in this proposal by investigation of the role of gonadal hormones in fear learning and extinction. Contrary to our original hypothesis, we saw no overall effect of gonadal hormones in any of our treatment groups (young female, young male, adult female, adult male). We did, howeve...
In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardiu... more In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. However, the genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-liker myocardial identity in the PV, is lacking in the SAN. Here we present evidence that Shox2 antagonizes the transcription output of Nkx2-5 in the PV myocardium and in a functional Nkx2-5(+) domain within the SAN to determine the cell fate. Shox2 deletion in the Nkx2-5(+) domain of the SAN caused sick sinus syndrome, associated with the loss of pacemaker program. Explanted Shox2(+) cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surroundin...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
A-type channels, encoded by the pore-forming alpha-subunits of the Kv4.x family, are particularly... more A-type channels, encoded by the pore-forming alpha-subunits of the Kv4.x family, are particularly important in regulating membrane excitability in the CNS and the heart. Given the key role of modulation of A currents by kinases, we sought to investigate the protein structure-function relationships underlying the regulation of these currents by PKA. We have previously shown the existence of two PKA phosphorylation sites in the Kv4.2 sequence; therefore, we focused this study on the Kv4.2 primary subunit. In the present studies we made the surprising finding that PKA phosphorylation of the Kv4.2 alpha-subunit is necessary but not sufficient for channel modulation; channel modulation by PKA required the presence of an ancillary subunit, the K+ channel interacting protein (KChIP3). Therefore, these findings indicate a surprising complexity to kinase regulation of A currents, in that an interaction of two separate molecular events, alpha-subunit phosphorylation and the association of an ...
Atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves o... more Atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. However, the genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. We have identified a Shox2-Nkx2-5 antagonistic mechanism that primes the pacemaking cell fate in the PV myocardium and SAN in the embryonic stage. Specifically, Shox2 deletion in the Nkx2-5+ domain of the SAN caused sick sinus syndrome, associated with the loss of pacemaker program. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. Shox2 interacts with Nkx2-5 directly, and a substantial genome wide co-occupan...
ABSTRACTThalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalam... more ABSTRACTThalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalamus to the cortex. In response to different physiological states and demands TCNs can fire in tonic and/or phasic burst modes. These firing properties of TCNs are supported by precisely timed inhibitory synaptic inputs from the thalamic reticular nucleus and intrinsic currents, including T-type Ca2+ and HCN currents. These intrinsic currents are mediated by Cav3.1 and HCN channel subunits, and alterations in expression or modulation of these channels can have dramatic implications on thalamus function. The factors that regulate these currents controlling the firing patterns important for integration of the sensory stimuli and the consequences resulting from the disruption of these firing patterns are not well understood. Shox2 is a transcription factor known to be important for pacemaker activity in the heart. We show here that Shox2 is also expressed in adult mouse thalamus. We hypothesi...
Boudaba, Cherif, Laura A. Schrader, and Jeffrey G. Tasker. Physiological evidence for local excit... more Boudaba, Cherif, Laura A. Schrader, and Jeffrey G. Tasker. Physiological evidence for local excitatory synaptic circuits in the rat hypothalamus. J. Neurophysiol. 77: 3396–3400, 1997. We conducted whole cell voltage-clamp and current-clamp recordings in slices of rat hypothalamus to test for local excitatory synaptic circuits. Local excitatory inputs to neurons of the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were studied with the use of electrical and chemical stimulation. Extracellular electrical stimulation provided indirect evidence of local excitatory circuits. Single stimuli evoked multiple excitatory postsynaptic potentials (EPSPs) or excitatory postsynaptic currents (EPSCs) in some PVN and SON cells, invoking polysynaptic excitatory inputs. Repetitive stimulation (10–20 Hz, 2–10 s) elicited long afterdischarges of EPSPs/EPSCs, suggesting a potentiation of upstream synapses in a polysynaptic circuit. Bath application of metabotropic glutamate receptor agonist...
The multiple memory systems hypothesis proposes that different types of learning strategies are m... more The multiple memory systems hypothesis proposes that different types of learning strategies are mediated by distinct neural systems in the brain. Male and female mice were tested on a water plus-maze task that could be solved by either a place or response strategy. One group of mice was pre-exposed to the same context as training and testing (PTC) and the other group was pre-exposed to a different context (PDC). Our results show that the PTC condition biased mice to place strategy use in males, but this bias was dependent on the presence of ovarian hormones in females.
ABSTRACT The question how neuronal systems process sensory information is as crucial for neurosci... more ABSTRACT The question how neuronal systems process sensory information is as crucial for neuroscience as it is for bio-inspired technical applications. Classification of multidimensional data is a common problem in signal and data analysis. The architecture of the olfactory system maps particularly well onto this problem [1]. Here, we present an olfaction-inspired spiking classifier network that achieves the performance of a Naive Bayes classifier on a benchmark data set, and demonstrate its ability to solve nonlinear classification problems. Moreover, we show an implementation of this network on a neuromorphic hardware system comprising 192 spiking analog hardware neurons embedded in digital control circuitry. Neuronal computations in this system operate at a speedup factor of 10^4 compared to biological real time, enabling high-thoughput neurocomputing. The neuromorphic implementation is subject to inherent device mismatch affecting analog components, e.g. neuron parameters, which leads to a decrease of classification performance. As a solution we present an algorithm for self-calibration that takes into account the specific architecture of our network in order to maximally exploit the capabilities of the hardware system. With this algorithm we were able to increase classifier performance on the hardware to a level comparable with a Naive Bayes classifier. As neuronal variation is not only a feature of neuromorphic hardware but also a hallmark of neurons in biological systems, our results provide insight into the biological relevance of neural coding hypotheses thought to operate on a neuronal substrate with heterogeneous sensitivity. References [1] Schmuker, M., and Schneider, G. (2007). Processing and classification of chemical data inspired by insect olfaction. Proc Natl Acad Sci U S A 104, 20285-20289.
American Journal of Physiology-Cell Physiology, 2005
Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the... more Kv4.2 is the primary pore-forming subunit encoding A-type currents in many neurons throughout the nervous system, and it also contributes to the transient outward currents of cardiac myocytes. A-type currents in the dendrites of hippocampal CA1 pyramidal neurons are regulated by activation of ERK/MAPK, and Kv4.2 is the likely pore-forming subunit of that current. We showed previously that Kv4.2 is directly phosphorylated at three sites by ERK/MAPK (T602, T607, and S616). In this study we determined whether direct phosphorylation of Kv4.2 by ERK/MAPK is responsible for the regulation of the A-type current observed in neurons. We made site-directed mutants, changing the phosphosite serine (S) or threonine (T) to aspartate (D) to mimic phosphorylation. We found that the T607D mutation mimicked the electrophysiological changes elicited by ERK/MAPK activation in neurons: a rightward shift of the activation curve and an overall reduction in current compared with wild type (WT). Surprising...
Transient outward K+ currents are particularly important for the regulation of membrane excitabil... more Transient outward K+ currents are particularly important for the regulation of membrane excitability of neurons and repolarization of action potentials in cardiac myocytes. These currents are modulated by PKC (protein kinase C) activation, and the K+- channel subunit Kv4.2 is a major contributor to these currents. Furthermore, the current recorded from Kv4.2 channels expressed in oocytes is reduced by PKC activation. The mechanism underlying PKC regulation of Kv4.2 currents is unknown. In the present study, we determined that PKC directly phosphorylates the Kv4.2 channel protein. In vitro phosphorylation of the intracellular N- and C-termini of Kv4.2 GST (glutathione transferase) tagged fusion protein revealed that the C-terminal of Kv4.2 was phosphorylated by PKC, whereas the N-terminal was not. Amino acid mapping and site-directed mutagenesis revealed that the phosphorylated residues on the Kv4.2 C-terminal were Ser447 and Ser537. A phospho-site-specific antibody showed that phosp...
Spatial memory processing requires functional interaction between the hippocampus and the medial ... more Spatial memory processing requires functional interaction between the hippocampus and the medial entorhinal cortex (MEC). The grid cells of the MEC are most abundant in layer II and rely on a complex network of local inhibitory interneurons to generate spatial firing properties. Stress can cause spatial memory deficits in males, but the specific underlying mechanisms affecting the known memory pathways remain unclear. Stress activates both the autonomic nervous system and the hypothalamic-pituitary-adrenal axis to release norepinephrine (NE) and glucocorticoids, respectively. Given that adrenergic receptor (AR) and glucocorticoid receptor (GR) expression is abundant in the MEC, both glucocorticoids and NE released in response to stress may have rapid effects on MEC-LII networks. We used whole-cell patch clamp electrophysiology in MEC slice preparations from male mice to test the effects of NE and glucocorticoids on inhibitory synaptic inputs of MEC-LII principal cells. Application o...
Post-traumatic stress disorder (PTSD) is characterized by memory disturbances following trauma. A... more Post-traumatic stress disorder (PTSD) is characterized by memory disturbances following trauma. Acute predator threat has emerged as an ethological model of PTSD, yet the effects of predator odor on signaling cascades associated with long-term memory remain poorly understood. In this study, we exposed male and female Wistar rats to the synthetic predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to assess behavioral and physiological responses as well as rapid modulation of signal transduction cascades associated with learning and memory in the male and female hippocampus. During exposure to TMT in the homecage, both male and female animals displayed robust immobility, avoidance, and altered activity as a function of time. Physiologically, TMT exposure increased circulating corticosterone and blood glucose in both male and female rodents, suggesting that TMT evokes sex-independent behavioral and physiological responses. With respect to signal transduction, TMT exposure rapidly reduced phosphorylation of cyclic-adenosine monophosphate response element binding protein (CREB) in the male, but not the female hippocampus. Furthermore, TMT exposure reduced phosphorylation of extracellular signal-regulated kinase 1/2 and increased nuclear expression of the synapto-nuclear messenger protein Jacob in the male hippocampus, consistent with activation of the CREB shut-off pathway. In a follow-up behavioral experiment, post-training exposure to TMT did not affect spatial water maze performance of male rats. However, male rats re-introduced to the context in which TMT had previously been presented displayed avoidance and hyperactivity, but not freezing behavior or elevated corticosterone responses, suggesting that TMT exposure supports a form of contextual conditioning which is not characterized by immobility. Taken together, our findings suggest that TMT evokes similar behavioral and physiological responses in male and female Wistar rats, but affects distinct signaling cascades in the male and female hippocampus which may contribute to behavioral disruptions associated with predator exposure.
Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal n... more Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks for proper brain function. Disruption of this balance during development may lead to autism spectral disorders and epilepsy. Synaptic excitation is counter-balanced by synaptic inhibition but also by regulation attenuation of cell-intrinsic neuronal excitability. To maintain proper excitation levels during development, neurons must sense activity over time and regulate the expression of genes that control these parameters. While this is a critical process, little is known about the transcription factors involved in coordinating gene expression to control excitatory/inhibitory (E/I) synaptic balance. We show here that the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both, in vitro and in vivo as shown by ex vivo analysis of a NeuroD2 KO mouse. Using micro...
This project investigates the role of gonadal hormones in the regulation of Pavlovian fear condit... more This project investigates the role of gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve as an animal model for the development of pathological fear in humans that suffer posttraumatic stress disorders and other anxiety disorders. Despite the increased incidence of PTSD and depressive disorders in women, the specific neurobiological mechanisms of gender differences of PTSD are poorly understood and very little basic research currently investigates this dichotomy. One possible hypothesis is that female hormones also play a role in predisposition to PTSD through epigenetic mechanisms. This concept is currently being tested in this proposal by investigation of the role of gonadal hormones in fear learning and extinction. Contrary to our original hypothesis, we saw no overall effect of gonadal hormones in any of our treatment groups (young female, young male, adult female, adult male). We did, howeve...
In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardiu... more In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. However, the genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-liker myocardial identity in the PV, is lacking in the SAN. Here we present evidence that Shox2 antagonizes the transcription output of Nkx2-5 in the PV myocardium and in a functional Nkx2-5(+) domain within the SAN to determine the cell fate. Shox2 deletion in the Nkx2-5(+) domain of the SAN caused sick sinus syndrome, associated with the loss of pacemaker program. Explanted Shox2(+) cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surroundin...
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2002
A-type channels, encoded by the pore-forming alpha-subunits of the Kv4.x family, are particularly... more A-type channels, encoded by the pore-forming alpha-subunits of the Kv4.x family, are particularly important in regulating membrane excitability in the CNS and the heart. Given the key role of modulation of A currents by kinases, we sought to investigate the protein structure-function relationships underlying the regulation of these currents by PKA. We have previously shown the existence of two PKA phosphorylation sites in the Kv4.2 sequence; therefore, we focused this study on the Kv4.2 primary subunit. In the present studies we made the surprising finding that PKA phosphorylation of the Kv4.2 alpha-subunit is necessary but not sufficient for channel modulation; channel modulation by PKA required the presence of an ancillary subunit, the K+ channel interacting protein (KChIP3). Therefore, these findings indicate a surprising complexity to kinase regulation of A currents, in that an interaction of two separate molecular events, alpha-subunit phosphorylation and the association of an ...
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Papers by Laura Schrader