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acetylcholine chloride [keywords]
- Signalling Molecules in the Urothelium. [REVIEW]
- Biomed Res Int 2014.:297295.
The urothelium was long considered to be a silent barrier protecting the body from the toxic effects of urine. However, today a number of dynamic abilities of the urothelium are well recognized, including its ability to act as a sensor of the intravesical environment. During recent years several pathways of these urothelial abilities have been proposed and a major part of these pathways includes release of signalling molecules. It is now evident that the urothelium represents only one part of the sensory web. Urinary bladder signalling is finely tuned machinery of signalling molecules, acting in autocrine and paracrine manner, and their receptors are specifically distributed among different types of cells in the urinary bladder. In the present review the current knowledge of the formation, release, and signalling effects of urothelial acetylcholine, ATP, adenosine, and nitric oxide in health and disease is discussed.
- Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease. [Journal Article]
- Front Aging Neurosci 2014.:213.
We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.
- C-07SPECT Imaging in Adults with Nicotine-Related Disorders. [Journal Article]
- Arch Clin Neuropsychol 2014 Sep; 29(6):575.
The study examined whether nicotine disorders affect cerebral blood flow at baseline and while concentrating.Two hundred and sixty two individuals with a diagnosis of a nicotine disorder and 94 healthy controls were given a single photon emission computed tomography (SPECT) scan as part of a comprehensive evaluation. Participants included 119 females, 236 males, and one unknown ranging from ages 18 to 84 with an average age of 35.7 (SD = 13.86). Baseline SPECT and SPECT while taking the Connors CPT (activation) were generated.An independent t-test was conducted, indicating a statistically significant (p < .001) increase in blood flow for individuals with nicotine disorders in the cerebellum, the occipital lobe, and the inferior, anterior region of the temporal lobe as well as the temporal pole at baseline. During the CPT, findings were consistent with baseline for the cerebellum and the temporal lobe, but not the occipital lobe.The SPECT imaging reveals that long-term nicotine use may activate the cerebellum and sections of every lobe, with the entire occipital lobe being stimulated; thus, nicotine appears to have a greater effect on the posterior and the inferior regions. The increased blood flow in the inferior region of the brain is more than likely due to the activation of the nicotinic receptors. This result suggests that chronic nicotine exposure may have an effect on the binding properties of nicotinic acetylcholine receptors. In addition, because of the increased amount of activation in the temporal lobe, these results indicate that nicotine may affect semantic processing.
- SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis. [JOURNAL ARTICLE]
- Biol Psychiatry 2014 Jul 24.
The neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.We used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.We show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.Our results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.
- SAR Studies on Carboxylic Acid Series M1 Selective Positive Allosteric Modulators (PAMs). [JOURNAL ARTICLE]
- Curr Top Med Chem 2014 Aug 26.
There is mounting evidence from preclinical and early proof-of-concept studies suggesting that selective modulation of the M1 muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD). A number of non-selective M1 muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M2 to M5 sub-types. Thus, there is a need to identify selective activators of the M1 receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M1 is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M1 receptor rather than the highly conserved orthosteric acetylcholine binding site. BQCA has been identified as a highly selective carboxylic acid M1 PAM and this review focuses on an extensive lead optimization campaign undertaken on this compound.
- Peripheral nervous system defects in a mouse model for peroxisomal biogenesis disorders. [JOURNAL ARTICLE]
- Dev Biol 2014 Aug 28.
Peroxisome biogenesis disorders (PBD) are autosomal recessive disorders in humans characterized by skeletal, eye and brain abnormalities. Despite the fact that neurological deficits, including peripheral nervous system (PNS) defects, can be observed at birth in some PBD patients including those with PEX10 mutations, the embryological basis of the PNS defects is unclear. Using a forward genetic screen, we identified a mouse model for Pex10 deficiency that exhibits neurological abnormalities during fetal development. Homozygous Pex10 mutant mouse embryos display biochemical abnormalities related to a PBD deficiency. During late embryogenesis, Pex10 homozygous mutant mice experience progressive loss of movement and at birth they become cyanotic and die shortly thereafter. Homozygous Pex10 mutant fetuses display decreased integrity of axons and synapses, over-extension of axons in the diaphragm and decreased Schwann cell numbers. Our neuropathological, molecular and electrophysiological studies provide new insights into the embryological basis of the PNS deficits in a PBD model. Our findings identify PEX10 function, and likely other PEX proteins, as an essential component of the spinal locomotor circuit.
- Interactions between Cholinergic and Fibroblast Growth Factor Receptors in Brain Trophism and Plasticity. [JOURNAL ARTICLE]
- Curr Protein Pept Sci 2014 Sep 1.
Acetylcholine, acting on both nicotinic receptors (nAChRs) and muscarinic receptors (mAChRs), plays a role in the regulation of synaptic plasticity, being involved in the regulation of cellular processes and cognitive functions, such as learning, memory and attention. Recently, G protein coupled receptors (GPCRs), including mAChRs, have been reported to transactivate tyrosine-kinase receptors (RTK), such as epidermal growth factor receptor (EGFR), and initiate their intracellular signaling. In this minireview we have first analysed the RTK transactivation mechanisms, involving cholinergic receptors, and thereafter the interplay between AChR and neurotrophic factor systems built up by FGF2 and fibroblast growth factor receptor 1 (FGFR1). Although mAChR and FGFR1 activate common signaling pathways, playing similar roles in the regulation of central nervous system (CNS) plasticity and trophism, this analysis revealed that at the present there are no data reporting an involvement of cholinergic receptors in the FGFR1 transactivation. However, here we reported preliminary results on FGFR1 transactivation by mAChRs, suggesting a possible interaction between mAChR and neurotrophic factor receptors, with potential relevance for cognitive functions.
- Autoantibodies at the neuromuscular junction - link to the central nervous system. [JOURNAL ARTICLE]
- Rev Neurol (Paris) 2014 Aug 28.
Antibodies to different membrane proteins, namely acetylcholine receptor, muscle specific kinase and low density lipoprotein receptor-related protein 4, at the neuromuscular junction are well recognised in myasthenia gravis, although the mechanisms responsible for the muscle distribution and fluctuations in function are still not very clear, and some of the issues are discussed below. In addition, the involvement of antibodies to the potassium channel complex proteins in neuromyotonia, help to lead to a better understanding of immunotherapy-responsive central nervous system diseases.
- α1 and α2 Adrenergic Responsiveness in Human Skeletal Muscle Feed Arteries: The Role of TRPV Ion Channels in Heat-induced Sympatholysis. [JOURNAL ARTICLE]
- Am J Physiol Heart Circ Physiol 2014 Aug 29.
The purpose of this study was to determine if heat inhibits α2-adrenergic vasocontraction, similarly to α1-adrenergic contraction, in isolated human skeletal muscle feed arteries (SMFA) and elucidate the role of the temperature-sensitive vanilloid type transient receptor potential (TRPV) ion channels in this response. Isolated SMFA from 37 subjects were studied using wire myography. α1 (phenylephrine, PE) and α2 (dexmedetomidine, DEX) contractions were induced at 37°C and 39°C with and without TRPV family and TRPV4-specific inhibition (ruthenium red (RR) and RN-1734, respectively). Endothelial function (acetylcholine, ACh) and smooth muscle function (sodium nitroprusside (SNP) and potassium chloride (KCl)) were also assessed under these conditions. Heat and TRPV inhibition was further examined in endothelium-denuded arteries. Contraction data are reported as a percentage of maximal contraction elicited by 100mM KCl (LTmax). DEX elicited a small and variable contractile response, one fifth the magnitude of PE, which was not as clearly attenuated when heated from 37°C to 39°C (12 ± 4 to 6 ± 2% LTmax; P=0.18) as were PE-induced contractions (59 ± 5 to 24 ± 4 % LTmax; P<0.05). Both forms of TRPV inhibition restored PE-induced contraction at 39°C (P<0.05) implicating these channels, particularly the TRPV4 channels, in the heat-induced attenuation of α-adrenergic vasocontraction. TRPV inhibition significantly blunted ACh relaxation while denudation prevented heat-induced sympatholysis without having an additive effect when combined with TRPV inhibition. In conclusion, physiological increases in temperature elicit a sympatholysis-like inhibition of α1-adrenergic vasocontraction in human SMFA that appears to be mediated by endothelial TRPV4 ion channels.
- Self-built microdialysis probes with improved recoveries of ATP and neuropeptides. [JOURNAL ARTICLE]
- J Neurosci Methods 2014 Aug 26.
Microdialysis is an established technique for collecting small molecular weight substances (e.g. neurotransmitter and energy metabolites) from the extracellular space. The major element of microdialysis is the probe which contains a semi-permeable membrane and is exposed to the interstitial space. As the microdialysis technique has major advantages, e.g. versatility and use in awake animals, commercially produced probes are in great demand. New Method: We here present the design of a probe assembly step by step which will enable researchers to build custom-made probes. Probe recoveries of substances with different molecular weight (ranging from 100-1,600Da) were compared for three different probes (CMA 12 Elite probe, custom-made 10k Da and 30kDa probes). Recoveries of glucose, lactate, acetylcholine, choline, ATP and the neuropeptides angiotensin II, substance P and somatostatin are presented.We found that the 10kDa probe is only useful for compounds up to 1,000Da while recoveries of the CMA-12 Elite Probe are variable and apparently dependent on ionic charges of analytes. The recovery of the custom-made 30kDa probe is highest and evidently not influenced by physicochemical parameters of analytes. In a further optimization step, we describe the use of ZipTip® μC-18 collection tips to replace the outlet tubing when purifying the dialysate for MALDI-MS measurements of neuropeptides.The results show that self-built microdialysis probes can be equally or more effective than commercially available probes.Self-built microdialysis probes with large pore-membranes are capable of dialyzing ATP and neuropeptides.