Journal of Physiology-London最新文献

The heart is an electrically controlled, mechanical pump that provides a constant supply of blood to the body. It is not surprising, then, that the heartbeat, which occurs on average one or twice every second and over 2.5 billion times without fail in most lifetimes, is maintained by a redundant and robust pacemaking system that ensures regular, rhythmic cardiac excitation. This excitation is initiated in the sinoatrial node (the heart's natural pacemaker), which displays intrinsic spontaneous electrical activity, responsible for the heart's automaticity. As part of the special issue on Pacemaking in Multicellular Organ Systems, in this review we provide a basic overview of the mechanisms responsible for cardiac automaticity intended for a general audience - to allow for comparison with other organs in which pacemaking activity is present - and discuss often overlooked factors critical for integrated cardiac pacemaker function. Ultimately, we hope that a better understanding of pacemaking in the heart, and how it relates to that seen in other organs, will improve our overall understanding of physiological cardiac function, automaticity observed in experimental model systems, and aberrant excitation responsible for deadly cardiac arrhythmias.

Lymphatic collecting vessels exhibit spontaneous phasic contractions that are critical for lymph propulsion and tissue fluid homeostasis. This rhythmic activity is driven by action potentials conducted across the lymphatic muscle cell (LMC) layer to produce entrained contractions. The contraction frequency of a lymphatic collecting vessel displays exquisite mechanosensitivity, with a dynamic range from <1 to >20 contractions per minute. A myogenic pacemaker mechanism intrinsic to the LMCs was initially postulated to account for pressure-dependent chronotropy. Further interrogation into the cellular constituents of the lymphatic vessel wall identified non-muscle cell populations that shared some characteristics with interstitial cells of Cajal, which have pacemaker functions in the gastrointestinal and lower urinary tracts, thus raising the possibility of a non-muscle cell pacemaker. However, recent genetic knockout studies in mice support LMCs and a myogenic origin of the pacemaker activity. LMCs exhibit stochastic, but pressure-sensitive, sarcoplasmic reticulum calcium release (puffs and waves) from IP₃R1 receptors, which couple to the calcium-activated chloride channel Anoctamin 1, causing depolarisation. The resulting electrical activity integrates across the highly coupled lymphatic muscle electrical syncytia through connexin 45 to modulate diastolic depolarisation. However, multiple other cation channels may also contribute to the ionic pacemaking cycle. Upon reaching threshold, a voltage-gated calcium channel-dependent action potential fires, resulting in a nearly synchronous calcium global calcium flash within the LMC layer to drive an entrained contraction. This review summarizes the key ion channels potentially responsible for the pressure-dependent chronotropy of lymphatic collecting vessels and various mechanisms of IP₃R1 regulation that could contribute to frequency tuning.

An increase in intracellular [Ca²⁺] in exocrine acinar cells resident in the salivary glands or pancreas is a fundamental event that drives fluid secretion and exocytosis of proteins. Stimulation with secretagogues initiates Ca²⁺ signals with precise spatiotemporal properties thought to be important for driving physiological output. Both in vitro, in acutely isolated acini, and in vivo, in animals expressing genetically encoded indicators, individual cells appear specialized to initiate Ca²⁺ signals upon stimulation. Furthermore, these signals appear to spread to neighbouring cells. These properties are present in the absence of a conventional pacemaker mechanism dependent on the cyclical activation of Ca²⁺-dependent or Ca²⁺-conducting plasma membrane ion channels. In this article, we propose a model for 'pacing' intracellular Ca²⁺ signals in acinar cells based on the enhanced sensitivity of a subpopulation of individual cells and the intercellular diffusion through gap junctions of inositol 1,4,5-trisphosphate and Ca²⁺ to neighbouring cells.

Despite widespread and striking examples of physiological oscillations, their functional role is often unclear. Even glycolysis, the paradigm example of oscillatory biochemistry, has seen questions about its oscillatory function. Here, we take a systems approach to argue that oscillations play critical physiological roles, such as enabling systems to avoid desensitization, to avoid chronically high and therefore toxic levels of chemicals, and to become more resistant to noise. Oscillation also enables complex physiological systems to reconcile incompatible conditions such as oxidation and reduction, by cycling between them, and to synchronize the oscillations of many small units into one large effect. In pancreatic $\beta$ -cells, glycolytic oscillations synchronize with calcium and mitochondrial oscillations to drive pulsatile insulin release, critical for liver regulation of glucose. In addition, oscillation can keep biological time, essential for embryonic development in promoting cell diversity and pattern formation. The functional importance of oscillatory processes requires a re-thinking of the traditional doctrine of homeostasis, holding that physiological quantities are maintained at constant equilibrium values, a view that has largely failed in the clinic. A more dynamic approach will initiate a paradigm shift in our view of health and disease. A deeper look into the mechanisms that create, sustain and abolish oscillatory processes requires the language of nonlinear dynamics, well beyond the linearization techniques of equilibrium control theory. Nonlinear dynamics enables us to identify oscillatory ('pacemaking') mechanisms at the cellular, tissue and system levels.

Many neurons in the mammalian brain show pacemaking activity: rhythmic generation of action potentials in the absence of sensory or synaptic input. Slow pacemaking of neurons releasing modulatory transmitters is easy to rationalize. More surprisingly, many neurons in the motor system also show pacemaking activity, often rapid, including cerebellar Purkinje neurons that fire spontaneously at 20-100 Hz, as well as key neurons in the basal ganglia, including subthalamic nucleus neurons and globus pallidus neurons. Although the spontaneous rhythmic firing of pacemaking neurons is phenomenologically similar to cardiac pacemaking, the underlying ionic mechanism in most neurons is quite different than for cardiac pacemaking. Few spontaneously active neurons rely on HCN 'pacemaker' channels for their activity. Most commonly, a central element is 'persistent' sodium current, steady-state subthreshold current carried by the same voltage-dependent sodium channels that underlie fast action potentials. Persistent sodium current is a steeply voltage-dependent current with a midpoint near -60 mV, which results in regenerative spontaneous depolarization once it produces a net inward current when summed with all other background currents, often at voltages as negative as -70 mV. This 'engine' of pacemaking is present in almost all neurons and must be held in check in non-pacemaking neurons by sufficiently large competing outward currents from background potassium channels. The intrinsic propensity of neurons to fire spontaneously underlies key normal functions such as respiration and generates the complex background oscillatory circuits revealed in EEGs, but can also produce out-of-control oscillations of overall brain function in epilepsy, ataxia and tremor.

Gastrointestinal (GI) organs display spontaneous, non-neurogenic electrical, and mechanical rhythmicity that underlies fundamental motility patterns, such as peristalsis and segmentation. Electrical rhythmicity (aka slow waves) results from pacemaker activity generated by interstitial cells of Cajal (ICC). ICC express a unique set of ionic conductances and Ca²⁺ handling mechanisms that generate and actively propagate slow waves. GI smooth muscle cells lack these conductances. Slow waves propagate actively within ICC networks and conduct electrotonically to smooth muscle cells via gap junctions. Slow waves depolarize smooth muscle cells and activate voltage-dependent Ca²⁺ channels (predominantly CaV1.2), causing Ca²⁺ influx and excitation-contraction coupling. The main conductances responsible for pacemaker activity in ICC are ANO1, a Ca²⁺-activated Cl^- conductance, and CaV3.2. The pacemaker cycle, as currently understood, begins with spontaneous, localized Ca²⁺ release events in ICC that activate spontaneous transient inward currents due to activation of ANO1 channels. Depolarization activates Ca_V3.2 channels, causing the upstroke depolarization phase of slow waves. The upstroke is transient and followed by a long-duration plateau phase that can last for several seconds. The plateau phase results from Ca²⁺-induced Ca²⁺ release and a temporal cluster of localized Ca²⁺ transients in ICC that sustains activation of ANO1 channels and clamps membrane potential near the equilibrium potential for Cl^- ions. The plateau phase ends, and repolarization occurs, when Ca²⁺ stores are depleted, Ca²⁺ release ceases and ANO1 channels deactivate. This review summarizes key mechanisms responsible for electrical rhythmicity in gastrointestinal organs.

Urine expulsion from the upper urinary tract is a necessary process that eliminates waste, promotes renal filtration and prevents nephron damage. To facilitate the movement of urine boluses throughout the upper urinary tract, smooth muscle cells that line the renal pelvis contract in a coordinated effort to form peristaltic waves. Resident pacemaker cells in the renal pelvis are critical to this process and spontaneously evoke transient depolarizations that initiate each peristaltic wave and establish rhythmic contractions. Renal pacemakers have been termed atypical smooth muscle cells due to their low expression of smooth muscle myosin and poor organization of myofilaments compared to typical (or contractile) smooth muscle cells that perform peristalsis. Recent findings discovered that pacemaker cells also express the tyrosine kinase receptor PDGFRα, enabling their identification and purification amongst other renal pelvis cell types. Improved identification methods have determined that the calcium-activated chloride channel, ANO1, is expressed by pacemaker cells and may contribute to spontaneous depolarization. A greater understanding of pacemaker and peristaltic mechanisms is warranted since aberrant contractile function may underlie diseases such as hydronephrosis, a deleterious condition that can cause significant and irreversible nephron injury.

Smooth muscle organs of the lower urinary tract comprise the bladder detrusor and urethral wall, which have a reciprocal contractile relationship during urine storage and micturition. As the bladder fills with urine, detrusor smooth muscle cells (DSMCs) remain relaxed to accommodate increases in intravesical pressure while urethral smooth muscle cells (USMCs) sustain tone to occlude the urethral orifice, preventing leakage. While neither organ displays coordinated regular contractions as occurs in small intestine, lymphatics or renal pelvis, they do exhibit patterns of rhythmicity at cellular and tissue levels. In rabbit and guinea-pig urethra, electrical slow waves are recorded from USMCs. This activity is linked to cells expressing vimentin, c-kit and Ca²⁺-activated Cl^- channels, like interstitial cells of Cajal in the gastrointestinal tract. In mouse, USMCs are rhythmically active (firing propagating Ca²⁺ waves linked to contraction), and this cellular rhythmicity is asynchronous across tissues and summates to form tone. Experiments in mice have failed to demonstrate a voltage-dependent mechanism for regulating this rhythmicity or contractions in vitro, suggesting that urethral tone results from an intrinsic ability of USMCs to 'pace' their own Ca²⁺ mobilization pathways required for contraction. DSMCs exhibit spontaneous transient contractions, increases in intracellular Ca²⁺ and action potentials. Consistent across numerous species, including humans, this activity relies on voltage-dependent Ca²⁺ influx in DSMCs. While interstitial cells are present in the bladder, they do not 'pace' the organ in an excitatory manner. Instead, specialized cells (PDGFRα⁺ interstitial cells) may 'negatively pace' DSMCs to prevent bladder overexcitability.