Postural instability via a loss of intermittent control in elderly and patients with Parkinson's disease: a model-based and data-driven approach

Postural instability is one of the major symptoms of Parkinson's disease. Here, we assimilated a model of intermittent delay feedback control during quiet standing into postural sway data from healthy young and elderly individuals as well as patients with Parkinson's disease to elucidate the possible mechanisms of instability. Specifically, we estimated the joint probability distribution of a set of parameters in the model using the Bayesian parameter inference such that the model with the inferred parameters can best-fit sway data for each individual. It was expected that the parameter values for three populations would distribute differently in the parameter space depending on their balance capability. Because the intermittent control model is parameterized by a parameter associated with the degree of intermittency in the control, it can represent not only the intermittent model but also the traditional continuous control model with no intermittency. We showed that the inferred parameter values for the three groups of individuals are classified into two major groups in the parameter space: one represents the intermittent control mostly for healthy people and patients with mild postural symptoms and the other the continuous control mostly for some elderly and patients with severe postural symptoms. The results of this study may be interpreted by postulating that increased postural instability in most Parkinson's patients and some elderly persons might be characterized as a dynamical disease

Functions of Muscarinic Receptor Subtypes in Gastrointestinal Smooth Muscle: A Review of Studies with Receptor-Knockout Mice

Parasympathetic signalling via muscarinic acetylcholine receptors (mAChRs) regulates gastrointestinal smooth muscle function. In most instances, the mAChR population in smooth muscle consists mainly of M2 and M3 subtypes in a roughly 80% to 20% mixture. Stimulation of these mAChRs triggers a complex array of biochemical and electrical events in the cell via associated G proteins, leading to smooth muscle contraction and facilitating gastrointestinal motility. Major signalling events induced by mAChRs include adenylyl cyclase inhibition, phosphoinositide hydrolysis, intracellular Ca2+ mobilisation, myofilament Ca2+ sensitisation, generation of non-selective cationic and chloride currents, K+ current modulation, inhibition or potentiation of voltage-dependent Ca2+ currents and membrane depolarisation. A lack of ligands with a high degree of receptor subtype selectivity and the frequent contribution of multiple receptor subtypes to responses in the same cell type have hampered studies on the signal transduction mechanisms and functions of individual mAChR subtypes. Therefore, novel strategies such as genetic manipulation are required to elucidate both the contributions of specific AChR subtypes to smooth muscle function and the underlying molecular mechanisms. In this article, we review recent studies on muscarinic function in gastrointestinal smooth muscle using mAChR subtype-knockout mice

A non-selective cationic channel activated by diacylglycerol in mouse intestinal myocytes

Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG), an analogue of diacylglycerol (DAG) formed via M_3 muscarinic receptors, induced inward cationic currents via a protein kinase C-independent mechanism and produced membrane depolarization with increased action potential discharges in mouse intestinal myocytes. Outside-out patches from the myocytes responded to OAG with openings of 115-pS channels characterized by a mean open time (O_τ) of 0.15 ms. M3 receptor stimulation is reportedly capable of causing brief openings (O_τ = 0.23 ms) of 120-pS cationic channels in intestinal myocytes, thus the present results strongly support the idea that the M_3-mediated 120-pS channel opening is brought about via DAG-dependent mechanisms