Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling

Abstract

Each heartbeat begins with the generation of an action potential in pacemaking cells in the sinoatrial node. This signal triggers contraction of cardiac muscle through a process termed excitation–contraction (EC) coupling. EC coupling is initiated in dyadic structures of cardiac myocytes, where ryanodine receptors in the junctional sarcoplasmic reticulum come into close apposition with clusters of CaV1.2 channels in invaginations of the sarcolemma. Cooperative activation of CaV1.2 channels within these clusters causes a local increase in intracellular Ca2+ that activates the juxtaposed ryanodine receptors. A salient feature of healthy cardiac function is the reliable and precise beat-to-beat pacemaking and amplitude of Ca2+ transients during EC coupling. In this review, we discuss recent discoveries suggesting that the exquisite reproducibility of this system emerges, paradoxically, from high variability at subcellular, cellular, and network levels. This variability is attributable to stochastic fluctuations in ion channel trafficking, clustering, and gating, as well as dyadic structure, which increase intracellular Ca2+ variance during EC coupling. Although the effects of these large, local fluctuations in function and organization are sometimes negligible at the macroscopic level owing to spatial–temporal summation within and across cells in the tissue, recent work suggests that the “noisiness” of these intracellular Ca2+ events may either enhance or counterintuitively reduce variability in a context-dependent manner. Indeed, these noisy events may represent distinct regulatory features in the tuning of cardiac contractility. Collectively, these observations support the importance of incorporating experimentally determined values of Ca2+ variance in all EC coupling models. The high reproducibility of cardiac contraction is a paradoxical outcome of high Ca2+ signaling variability at subcellular, cellular, and network levels caused by stochastic fluctuations in multiple processes in time and space. This underlying stochasticity, which counterintuitively manifests as reliable, consistent Ca2+ transients during EC coupling, also allows for rapid changes in cardiac rhythmicity and contractility in health and disease.

The formation of KV2.1 macro-clusters is required for sex-specific differences in L-type CaV1.2 clustering and function in arterial myocytes

“…Our finding that the size distributions of KV2.1WT and KV2.1S586A clusters could be described by exponential functions, the hallmark of a Poisson process, suggests that these clusters are formed stochastically 29 . To test this hypothesis, we implemented the stochastic modeling approach employed by Sato et al 9 to determine whether we could reproduce our cluster distributions and make testable predictions regarding plasma membrane protein organization.…”

A computational model predicts sex-specific responses to calcium channel blockers in mammalian mesenteric vascular smooth muscle

“…First , the analysis suggests that small differences in the number of K V 2.1 and Ca V 1.2 channels can translate into large, functionally important differences in membrane potential and [Ca 2+ ] i and hence affect and control myogenic tone under physiological and pathological conditions. Second , the small number of K V 2.1 and Ca V 1.2 channels gating between −40 and −30 mV likely makes smooth muscle cells more susceptible to stochastic fluctuations in the number and open probabilities of these channels than in cells where a large number of channels regulate membrane excitability and Ca 2+ influx (e.g., adult ventricular myocyte 78 ). This, at least in part, likely contributes to Ca 2+ signaling heterogeneity in vascular smooth muscle.…”

What makes the sinoatrial node tick? A question not for the faint of heart

“…AP-induced calcium transients in some cells within the SAN are not synchronized to the AP rate and rhythm recorded in the atria [20]. Thus, expansion of the frontier of knowledge about the heart's pacemaker requires new understanding of how these local, heterogeneous, Ca 2+ behaviours within and among SAN cells become organized into a highly synchronized impulse that exits the SAN at fairly regular intervals to initiate the heartbeat [89,90].

Figure 3( a ) A mouse SAN preparation imaged at 5× magnification, with red colour indicating Ca 2+ -induced Fluo-4 fluorescence during an action potential (AP) cycle.

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“…This heterogeneity, alongside the loose electrical coupling of cells in the meshwork of HCN4 + /CX43 − cells in the central SAN, indicates that pacemaking is an emergent property of the entire tissue, irreducible to the activity of any given cell within it [20]. The self-ordering process by which spatio-temporally asynchronous signals in different areas of the tissue give rise to the relatively rhythmic impulse that exits the SAN is yet to be understood [89,90]. Part of the answer may be that neurotransmitter-mediated communication in the node is not limited to acetylcholine and adrenaline, as it also includes nitric oxide [79], glutamate [91], GABA [92], serotonin [93] and neuropeptide Y [79].…”