Muscarinic M1, M3, Nicotinic,GABAA and GABAB Receptor ...

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signals (Zawalich & Rasmussen, 1990). While the preeminent nutrient fuel that regulates secretion is glucose, it is also clear that the vagally derived signal acetylcholine plays an important role (Shiota et al., 2002). The underlying explanation for impaired insulin secretion in diabetes resides, in the inability of glucose to activate information flow in the phospholipase C/protein kinase C (PLC/PKC) signal transduction system to the same quantitative extent in mouse islets as it does in rat and, presumably, human islets as well. Our study showed a decreased expression of phospholipase C expression in the pancreatic islets of hypoglycemia and diabetic rats which shows that hypoglycemia and the subsequent glucose deprivation adversely affects the pancreatic second messenger enzyme regulation. The impact of acetylcholine on the β cell is initiated by the interaction of the neurotransmitter with the muscarinic cholinergic receptor, the activation of phospholipase C and the subsequent generation of inositol phosphates and diacylglycerol (Berridge, 1987; Gilon &. Henquin, 2001). The decreased phospholipase C expression is associated with impaired cholinergic and GABAergic eceptor signaling during hypoglycemia and hyperglycemia. Cholinergic stimulation of the β cell activates the insulin secretory process, a response that is mediated by PLC (Kelley et al., 1995). The nature of the receptor type that couples the activation of PLC to release has yet to be precisely determined and both the muscarinic M1 and M3 receptor types appear to be expressed in the β cell (Lismaa et al., 2000). Our study on PLC expression shows that glucose deprivation is detrimental to innate insulin secreting function and other functions associated with pancreas. Thus, hypoglycemia exacerbates the dysfunction caused by diabetes. CREB PROTEIN EXPRESSION IN BRAIN OF EXPERIMENTAL RATS The cAMP responsive element binding protein (CREB) is a nuclear protein that modulates the transcription of genes with cAMP responsive elements in their promoters. CREB is a basally expressed, post-translationally activated 143
144 Discussion transcription factor that has been implicated in the trans-activation of a number of genes in response to cAMP and calcium signals. This transcription factor is a component of intracellular signaling events that regulate a wide range of biological functions, from spermatogenesis to circadian rhythms and memory. Interruption of CREB phosphorylation pathway interferes with important cognitive performance and behavioural aspects associated with CNS. Current study showed a significant down regulation of CREB in cerebral cortex, cerebellum, brainstem, hippocampus and up regulated expression in corpus striatum of diabetic rats when compared to control. Recurrent hypoglycemia caused further decrease in the CREB expression in all the brain regions studied which showed a significant decreased CREB transcription in hypoglycemic and diabetic – hyperglycemic condition. Interruption of CREB phosphorylation pathway interferes with important cognitive performance and behavioural aspects associated with CNS. Alterations in CREB-mediated transcription have been implicated in multiple cognitive and psychiatric disorders including depression, anxiety, addiction, and cognitive decline and reports show decreased CREB activity in the brains of depressed patients (Mayr & Montminy, 2001). Schwechter et al., (2003) reported susceptibility to seizures positively correlated with blood glucose concentrations as the increased glucose concentration was associated with proconvulsant effects. As previously reported, forebrain susceptibility to seizures is increased during moderate in vivo hypoglycemia and the hippocampus is involved during hypoglycemic seizures during glucose deprivation (Kirchner et al., 2006). CREB phosphorylation is decreased by seizures in experimental animals. Therefore our studies on CREB mRNA expression in hypoglycemic and hyperglycemic rats suggest the correlation of decreased expression of CREB to seizures induced by variation in glucose metabolism. To conclude, our results on hypoglycemic and hyperglycemic changes at molecular level showed that both conditions adversely affect the neuronal cells. The alterations in cholinergic, GABAergic receptors and subsequent changes of
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MUSCARINIC M1, M3, NICOTINIC, GABAA
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ACKNOWLEDGEMENT To the Almighty God
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Seema Chandran, Ms. Neema Ani Manga
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ABBREVIATIONS 5-HIAA 5 Hydroxy indo
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PFC Prefrontal cortex PLC Phospholi
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GABAC Receptors 34 Glutamic Acid De
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Behavioural response of control and
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the cerebral cortex of control and
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Muscarinic M1 receptor analysis Sca
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REAL TIME-PCR ANALYSIS 81 Real Time
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Real Time PCR analysis of GABAAα1
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pancreas of control and experimenta
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utilization is decreased in the bra
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impairment, coma or seizure (Cryer,
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achieving optimal blood sugar contr
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OBJECTIVES OF THE PRESENT STUDY 1.
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Literature Review Diabetes mellitus
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12 Literature Review from the adren
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14 Literature Review Hypoglycemic c
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16 Literature Review respectively)
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18 Literature Review in extracellul
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20 Literature Review substrates in
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22 Literature Review nucleus, altho
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24 Literature Review al., 1990; Lev
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26 Literature Review muscarinic M2
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Signal transduction by muscarinic a
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30 Literature Review nicotinic acet
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GABAA Receptors 32 Literature Revie
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34 Literature Review GABAB-mediated
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36 Literature Review (Erlander et a
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38 Literature Review which could be
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40 Literature Review administration
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42 Literature Review the hippocampu
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44 Literature Review understanding
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Confocal Dyes Rat primary antibody
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antipyryl)-p-benzo quinoneimine. Th
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was analyzed. Data was expressed as
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ANALYSIS OF THE RECEPTOR BINDING DA
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Taqman probes of muscarinic M1, M3,
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Taylor, 1968). The islets were isol
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Results BODY WEIGHT AND BLOOD GLUCO
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60 Results IIH and C + IIH rats sho
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Real Time-PCR analysis of muscarini
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Real Time PCR analysis of SOD 64 Re
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66 Results GABAAα1 receptor antibo
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68 Results compared to diabetic gro
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70 Results compared to diabetic rat
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72 Results Muscarinic M3 receptor a
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Muscarinic M3 receptor analysis 74
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76 Results group, α7 nAChR mRNA si
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78 Results diabetic rats. In C + II
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Muscarinic M1 receptor analysis 80
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Real Time-PCR analysis of α7 nAChR
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Real Time PCR analysis of phospholi
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HIPPOCAMPUS Total muscarinic recept
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88 Results IIH and C + IIH group sh
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90 Results group, GLUT3 mRNA signif
Page 117 and 118: 92 Results α7 nACh receptor antibo
Page 119 and 120: GABA receptor analysis 94 Results S
Page 121 and 122: 96 Results control. D + IIH and C +
Page 123 and 124: Discussion Glucose is the principal
Page 125 and 126: 100 Discussion The ability to sense
Page 127 and 128: 102 Discussion The Y-maze test is a
Page 129 and 130: 104 Discussion CHOLINERGIC ENZYME A
Page 131 and 132: 106 Discussion Pancreas Insulin sec
Page 133 and 134: 108 Discussion 2003). Cholinergic m
Page 135 and 136: 110 Discussion brain for learning,
Page 137 and 138: 112 Discussion hypoglycemia on brai
Page 139 and 140: 114 Discussion shows impaired expre
Page 141 and 142: 116 Discussion glycemic control is
Page 143 and 144: 118 Discussion release (Ilcol et al
Page 145 and 146: 120 Discussion al., 1992), it has t
Page 147 and 148: 122 Discussion metabolic cycles are
Page 149 and 150: 124 Discussion al., 1988). Low bloo
Page 151 and 152: 126 Discussion modulate the second
Page 153 and 154: 128 Discussion between excitation a
Page 155 and 156: 130 Discussion hypoglycemic seizure
Page 157 and 158: 132 Discussion Insulin secretion fr
Page 159 and 160: 134 Discussion hyper and hypoglycem
Page 161 and 162: 136 Discussion receptors in glucose
Page 163 and 164: 138 Discussion exacerbated by recur
Page 165 and 166: 140 Discussion Haces et al., 2010).
Page 167: 142 Discussion hypoglycemic and dia
Page 171 and 172: Summary 1. Insulin induced hypoglyc
Page 173 and 174: 148 Summary specific antibodies con
Page 175 and 176: 150 Summary 16. Transcription facto
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Body weight (gm) 300 250 200 150 10
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Figure-3 Blood glucose levels at di
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Figure-5 Behavioural response of co
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Figure-7 Scatchard analysis of [ 3
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Figure-11 Real Time PCR amplificati
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C D + IIH Figure--25 Muscarinic M1
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Figure--27 α 7 nACh receptor expre
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Figure--47 Muscarinic M1 receptor e
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Figure--49 α7 nicotinic acetylchol
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Figure--71 α7 nicotinic acetylchol
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C Figure--93 GABAAα1 receptor expr
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Figure-101 Real Time PCR amplificat
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Figure—113 Muscarinic M3 receptor
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Figure--115 GABAAα1 receptor expre
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Figure-117 Scatchard analysis of [
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Figure-119 Scatchard analysis of [
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Figure-131 Muscarinic M1 receptor e
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C D + IIH Figure-133 GABAAα1 recep
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