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Development (Cambridge, England) (1)
The Journal of General Physiology (1)
The Journal of neuroscience : the official journal of the Society for Neuroscience (1)
Polo-Parada, Luis (3)
Alibhai, Aziza (1)
Ehler, Elisabeth (1)
Emes, Richard D. (1)
Korn, Stephen J. (1)
Landmesser, Lynn T. (1)
Loughna, Siobhan (1)
Patel, Bhakti (1)
Rutland, Catrin Sian (1)
Suren, Suganthi (1)
Thorpe, Aaran (1)
Wang, Sheng (1)
Year of Publication
Knockdown of embryonic myosin heavy chain reveals an essential role in the morphology and function of the developing heart
Rutland, Catrin Sian
Emes, Richard D.
Development (Cambridge, England)
The expression and function of embryonic myosin heavy chain (eMYH) has not been investigated within the early developing heart. This is despite the knowledge that other structural proteins, such as alpha and beta myosin heavy chains and cardiac alpha actin, play crucial roles in atrial septal development and cardiac function. Most cases of atrial septal defects and cardiomyopathy are not associated with a known causative gene, suggesting that further analysis into candidate genes is required. Expression studies localised eMYH in the developing chick heart. eMYH knockdown was achieved using morpholinos in a temporal manner and functional studies were carried out using electrical and calcium signalling methodologies. Knockdown in the early embryo led to abnormal atrial septal development and heart enlargement. Intriguingly, action potentials of the eMYH knockdown hearts were abnormal in comparison with the alpha and beta myosin heavy chain knockdowns and controls. Although myofibrillogenesis appeared normal, in knockdown hearts the tissue integrity was affected owing to apparent focal points of myocyte loss and an increase in cell death. An expression profile of human skeletal myosin heavy chain genes suggests that human myosin heavy chain 3 is the functional homologue of the chick eMYH gene. These data provide compelling evidence that eMYH plays a crucial role in important processes in the early developing heart and, hence, is a candidate causative gene for atrial septal defects and cardiomyopathy.
Atrial septal development; Cardiomyopathy; Myosin; Chick
Characterization of rhythmic Ca2+ transients in early embryonic chick motoneurons: Ca2+ sources and effects of altered activation of transmitter receptors
Landmesser, Lynn T.
The Journal of neuroscience : the official journal of the Society for Neuroscience
In the nervous system, spontaneous Ca2+ transients play important roles in many developmental processes. We previously found that altering the frequency of rhythmic spontaneous bursting episodes in embryonic chick spinal cords differentially perturbed the two main pathfinding decisions made by motoneurons, dorsal-ventral and pool-specific, depending on the sign of the frequency alteration. Here, we characterized the Ca2+ transients associated with these bursts, showing that at early stages while motoneurons are still migrating and extending axons to the base of the limb bud, they display spontaneous, highly rhythmic, and synchronized Ca2+ transients, as did some precursor cells in the ependymal layer. T-type Ca2+ channels and a persistent Na+ current were essential to initiate spontaneous bursts and associated transients, but subsequent propagation of activity throughout the cord resulted from network driven chemical transmission mediated presynaptically by Ca2+ entry through N-type Ca2+ channels and postsynaptically by acetylcholine acting on nicotinic receptors. The increased [Ca2+]i during transients depended primarily on L-type and T-type channels with a modest contribution from TRP channels and ryanodine sensitive internal stores. Significantly, the drugs used previously to produce pathfinding errors altered transient frequency but not duration or amplitude. These observations imply that the different transient frequencies may differentially modulate motoneuron pathfinding. In addition, the duration of the Ca2+ transients differed significantly between pools, potentially enabling additional distinct pool-specific downstream signaling. Many early events in spinal motor circuit formation are thus potentially sensitive to the rhythmic Ca2+ transients we have characterized and to any drugs that perturb them.
Ca2+ channels; calcium induced calcium release; nicotinic receptors; GABAA receptors; persistent Na+ current; spontaneous activity
Block of N-type Calcium Channels in Chick Sensory Neurons by External Sodium
Korn, Stephen J.
The Journal of General Physiology
L-type Ca2+ channels select for Ca2+ over sodium Na+ by an affinity-based mechanism. The prevailing model of Ca2+ channel permeation describes a multi-ion pore that requires pore occupancy by at least two Ca2+ ions to generate a Ca2+ current. At [Ca2+] < 1 μM, Ca2+ channels conduct Na+. Due to the high affinity of the intrapore binding sites for Ca2+ relative to Na+, addition of μM concentrations of Ca2+ block Na+ conductance through the channel. There is little information, however, about the potential for interaction between Na+ and Ca2+ for the second binding site in a Ca2+ channel already occupied by one Ca2+. The two simplest possibilities, (a) that Na+ and Ca2+ compete for the second binding site or (b) that full time occupancy by one Ca2+ excludes Na+ from the pore altogether, would imply considerably different mechanisms of channel permeation. We are studying permeation mechanisms in N-type Ca2+ channels. Similar to L-type Ca2+ channels, N-type channels conduct Na+ well in the absence of external Ca2+. Addition of 10 μM Ca2+ inhibited Na+ conductance by 95%, and addition of 1 mM Mg2+ inhibited Na+ conductance by 80%. At divalent ion concentrations of 2 mM, 120 mM Na+ blocked both Ca2+ and Ba2+ currents. With 2 mM Ba2+, the IC50 for block of Ba2+ currents by Na+ was 119 mM. External Li+ also blocked Ba2+ currents in a concentration-dependent manner, with an IC50 of 97 mM. Na+ block of Ba2+ currents was dependent on [Ba2+]; increasing [Ba2+] progressively reduced block with an IC50 of 2 mM. External Na+ had no effect on voltage-dependent activation or inactivation of the channel. These data suggest that at physiological concentrations, Na+ and Ca2+ compete for occupancy in a pore already occupied by a single Ca2+. Occupancy of the pore by Na+ reduced Ca2+ channel conductance, such that in physiological solutions, Ca2+ channel currents are between 50 and 70% of maximal.
calcium channels; ion channel selectivity; sodium; permeation
Results 1-3 (3)
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