Browsing by Subject "Intracellular calcium channels"
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Item Function of Differentially Expressed Intracellular Calcium Channels in Retinal Neurons(2008-05-01) Nixon, Everett Sheldon; Peter Koulen; Raghu Krishnamoorthy; Rong MaNixon, Everett, Function of differentially expressed intracellular calcium channels in retinal neurons. Doctor of Philosophy (Pharmacology and Neuroscience), May, 2008, pp154, 17 illustrations. The retina, a specialized part of the central nervous system (CNS) is the innermost layer of the eye responsible for capturing light and converting the light response into a signal that can be transmitted through the optic nerve and onto the brain for interpretation. The ability of the retina to perceive light is dependent on its sensory neurons and the neural circuitry present that initiate the primary stage of processing the image being visualized, which then transmits an electrical signal down the optic nerve to the brain for processing and ultimately visual perception. In the vertical pathway of the visual process that involves the photoreceptor cells, bipolar cells and the ganglion cells, glutamate is the main excitatory neurotransmitter. Communication between these cells is dependent upon the release of glutamate into the synaptic region within both the outer plexiform layer and inner plexiform layer, a process that is Ca2+ regulated. In neurons, Ca2+ regulates a plethora of processes such as gene expression, cell death, synaptic plasticity and neurotransmitter release since it serves as a critical intracellular messenger. In view of the involvement of Ca2+ in a variety of physiological processes, it is essential for the intracellular Ca2+ concentration to be tightly regulated within neuronal cell. Regulation of Ca2+ signaling within retinal neurons can occur via inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyRs). These receptors are involved in the release of Ca2+ from the intracellular stores such as the endoplasmic reticulum (ER) into the cytosol. IP3Rs and RyRs contribute substantially to cytosolic free Ca2+ concentration transients and thereby play an important role in neuronal function. The purpose of the study was to determine the role of mGluRs, IP3Rs and RyRs in increasing intracellular Ca2+ levels in retinal neurons as related to signaling and neurotransmitter release. The present study provides experimental evidence for the following mechanisms: -Activation of mGluR8 in photoreceptor cells reduced cytosolic Ca2+ concentration by inhibition of the voltage gated Ca2+ channels on the plasma membrane. –The distribution of IP3R and RyR isoforms was associated with cytosolic Ca2+ transients and the IP3R induced transients occurs by activation of group I mGluRs. –In rod bipolar cells, the main increase in cytosolic Ca2+ concentrations during depolarization is due to Ca2+ release from internal stores via activation of RyR. The results of the present study contribute to the understanding of intracellular Ca2+ signaling in retinal neurons and Ca2+ signaling mechanisms. This is of relevance for identifying mechanisms controlling neurotransmitter release and possible pharmacological targets in neurodegenerative retinal diseases characterized by Ca2+ dyshomeostasis.Item Regulation of intracellular calcium channels by their associated proteins homer 1 and presenilin 1(2006-05-01) Hwang, Sung-Yong; Koulen, Peter; Dillon, Glenn; Singh, MeharvanSung-Yong, Hwang, Regulation of intracellular calcium channels by their associated proteins homer 1 and presenilin 1. Doctor of Philosophy (Pharmacology and Neuroscience), May, 2006, 184 pp., 4 tables, 20 illustrations, 74 titles. In neurons, Calcium (CA2+) serves as a critical intracellular messenger that regulates a variety of cellular processes such as gene expression, neurotransmitter release, cell death, and synaptic plasticity. Therefore, it is essential for neurons to control their Ca2+ levels tightly. Ca2+ is released within the cell from intracellular stores such as the endoplasmic reticulum by activation of intracellular Ca2+ channels (ICCs) such as the inositol 1,4,5-triphosphate (IP3) receptors (IP3Rs) and ryanodine receptors (RyRs). Each of these two groups of ICC has three isoforms. A number of associated proteins of these two ICCs that were shown to modulate activity of the respective channel have been identified. Homer 1, a synaptic scaffolding protein not only physically associated with IP3R type1 (IP3R1), but also changes the activity of IP3R1, suggesting that Homer 1 is involved in intracellular Ca2+ signaling. Based on the similarity in amino acid sequence and molecular and physiological properties among IP3R isoforms and the fact that IP3R type 3 (IP3R3) contains the proline-rich motif (PPxxFr) that is required for the interaction with Homer, it was hypothesized that Homer 1 associates with IP3R3, leading to changes in the channel activity. Presenilin 1 (PS1) is a transmembrane protein, being expressed in cell body, dendrites, and axon in the neuron. Mutations in PS1 account for most cases of early-onset familial Alzheimer’s disease (AD). PS1 was shown to associate with RyRs and to modulate their channel activity. Therefore, it was hypothesized that specific regions of PS-1 bind to RyR type 2 (RyR2), a major isoform in the brain, resulting in changes in the channel activity. Homer 1c was shown to associate with IP3R3, leading to a decrease in channel activity. A specific region of PS1 that interacts with RyR2 was identified to increase the channel activity of RyR2. Results of the present study contributed to the understanding of the nature of intracellular Ca2+ signaling as well as the mechanisms of action by which ICCs are regulated by their associated proteins. These findings provide the rationale for novel strategies to study neurological disorders including AD and epilepsy that are mediated by Ca2+ dysregulation.