Barbieri, Riccardo, Eric C. Matten, AbdulRasheed A. Alabi, and Emery N. Brown. A point-process model of human heartbeat intervals: new definitions of heart rate and heart rate variability. Am J Physiol Heart Circ Physiol 288: H424 -H435, 2005. First published September 16, 2004; 10.1152/ajpheart.00482.2003.-Heart rate is a vital sign, whereas heart rate variability is an important quantitative measure of cardiovascular regulation by the autonomic nervous system. Although the design of algorithms to compute heart rate and assess heart rate variability is an active area of research, none of the approaches considers the natural point-process structure of human heartbeats, and none gives instantaneous estimates of heart rate variability. We model the stochastic structure of heartbeat intervals as a history-dependent inverse Gaussian process and derive from it an explicit probability density that gives new definitions of heart rate and heart rate variability: instantaneous R-R interval and heart rate standard deviations. We estimate the time-varying parameters of the inverse Gaussian model by local maximum likelihood and assess model goodness-of-fit by Kolmogorov-Smirnov tests based on the time-rescaling theorem. We illustrate our new definitions in an analysis of human heartbeat intervals from 10 healthy subjects undergoing a tilt-table experiment. Although several studies have identified deterministic, nonlinear dynamical features in human heartbeat intervals, our analysis shows that a highly accurate description of these series at rest and in extreme physiological conditions may be given by an elementary, physiologically based, stochastic model. tilt table; inverse Gaussian; time-rescaling theorem; KolmogorovSmirnov test; autonomic regulation HEART RATE IS A VITAL moment-to-moment indicator of cardiovascular integrity measured on every physical examination. Heart rate is also monitored continuously in patients under anesthesia during surgery and in those treated in an intensive care unit, as well as in fetuses during labor. Heart rate variability is an important quantitative marker of cardiovascular regulation by the autonomic nervous system. Its significance was first appreciated over 40 years ago, when it was discovered that fetal distress is associated with appreciable changes in heart rate variability before any change in heart rate (27). Physicians routinely use Holter monitor studies, i.e., 24 -72 h of continuous electrocardiography, in which heart rate variability is assessed to diagnose diseases that affect the autonomic nervous system, follow their progression, and measure the efficacy of therapy. Such diseases include diabetes, GuillainBarre syndrome, multiple sclerosis, Parkinson's disease, and Shy-Drager orthostatic hypotension (17,19,32,38). Loss of heart rate variability is an independent predictor of mortality after an acute myocardial infarction (6,33,35), is indicative of ventricular dysfunction in patients with congestive heart failure (41, 42), and is associated with fetal distress during labor ...

Voltage-sensing domains enable membrane proteins to sense and react to changes in membrane voltage. Although identifiable S1-S4 voltage-sensing domains are found in an array of conventional ion channels and in other membrane proteins that lack pore domains, the extent to which their voltage sensing mechanisms are conserved is unknown. Here we show that the voltage-sensor paddle, a motif composed of S3b and S4 helices, can drive channel opening with membrane depolarization when transplanted from an archaebacterial voltage-activated potassium (Kv) channel (KvAP) or voltagesensing domain proteins (Hv1 and Ci-VSP) into eukaryotic Kv channels. Tarantula toxins that partition into membranes can interact with these paddle motifs at the protein-lipid interface and similarly perturb voltage sensor activation in both ion channels and voltage-sensing domain proteins. Our results show that paddle motifs are modular, that their functions are conserved in voltage sensors, and that they move in the relatively unconstrained environment of the lipid membrane. The widespread targeting of voltage-sensor paddles by toxins demonstrates that this modular structural motif is an important pharmacological target.Ion channels that open and close in response to changes in membrane voltage have a modular architecture, with a central pore domain that determines ion selectivity, and four surrounding voltage sensing domains that move in response to changes in membrane voltage to drive opening of the pore 1-5 (Fig 1a). Although X-ray structures have now been solved for two voltage-activated potassium (Kv) channels 1, 6-9 , the structural basis of voltage sensing remains controversial 10-12 . A seminal observation in the X-ray structures of the KvAP channel, an archaebacterial Kv channel from Aeropyrum pernix, was that the S3b helix and the charge-bearing S4 helix within the voltage-sensing domain form a helix-turn-helix structure, termed the paddle motif 1, 8, 9 . Studies on KvAP 1, 9, 13-16 suggest that this voltage-sensor paddle is buried in the membrane and that it moves at the protein-lipid interface, which contrasts with models for eukaryotic Kv channels where the S4 helix is protected from membrane lipids by other regions of the protein 10-12, 17-21 . Voltage-sensing domains have also recently been described in voltage-sensing proteins that lack associated pore domains 5, 22, 23 . In Ci-VSP the voltage-sensing domain is coupled to a phosphatase domain and in Hv1 the voltage-sensing domain itself is thought to function as a proton channel. Here we explore whether the mechanisms of voltage-sensing are conserved between the distantly related eukaryotic and Chimeras between Kv channelsWe began by generating chimeras between the archaebacterial KvAP channel 24 and the eukaryotic Kv2.1 channel from rat brain 25 to define the interchangeable regions. Transfer of the KvAP pore domain into Kv2.1 results in channels that open in response to membrane depolarization (Fig 1a ; Supplementary Fig 1 and Table 1), so long as the S4-S5 linker hel...

Regulated exocytosis and endocytosis are critical to the function of many intercellular networks, particularly the complex neural circuits underlying mammalian behavior. Kiss-and-run (KR) is an unconventional fusion between secretory vesicles and a target membrane that releases intravesicular content through a transient, nanometer-sized fusion pore. The fusing vesicle retains its gross shape, precluding full integration into the planar membrane, and enough molecular components for rapid retrieval, reacidification, and reuse. KR makes judicious use of finite presynaptic resources, and mounting evidence suggests that it influences synaptic information transfer. Here we detail emerging perspectives on KR and its role in neurotransmission. We additionally formulate a restraining force hypothesis as a plausible mechanistic basis for KR and its physiological modulation in small nerve terminals. Clarification of the mechanism and function of KR has bearing on understanding the kinetic transitions underlying SNARE-mediated fusion, interactions between vesicles and their local environment, and the influence of release dynamics on neural information processing.

Synaptic vesicles release neurotransmitter at chemical synapses, thus initiating the flow of information in neural networks. To achieve this, vesicles undergo a dynamic cycle of fusion and retrieval to maintain the structural and functional integrity of the presynaptic terminals in which they reside. Moreover, compelling evidence indicates these vesicles differ in their availability for release and mobilization in response to stimuli, prompting classification into at least three different functional pools. Ongoing studies of the molecular and cellular bases for this heterogeneity attempt to link structure to physiology and clarify how regulation of vesicle pools influences synaptic strength and presynaptic plasticity. We discuss prevailing perspectives on vesicle pools, the role they play in shaping synaptic transmission, and the open questions that challenge current understanding.