Making a case, for who is setting the pace: conductors, drummers or just jamming in multicellular organ systems?

The body is filled with organ systems that generate spontaneous, rhythmic behaviours, such as the regular electrical excitation that causes the beating of the heart, neuronal firing in the brain leading to generation of thoughts and actions, phasic contractions of the gut to allow for digestion or timed contractions of the myometrium to accommodate a growing fetus. These patterns of activity are often well co-ordinated, and disruptions in their regularity or frequency (or ‘pace’) can lead to arrhythmias, seizures, dysmotility or preterm labour. Many of these rhythmic processes occur without our conscious knowledge, thus begging the question: who is setting the pace? This is especially challenging to answer in physiological systems consisting of complex, multicellular populations. Are there ‘pacemaker’ cells that act as conductors to an orchestra (i.e. do not play music themselves but cue other cells to perfectly co-ordinate performances)? Do some pacemaker cells act like drummers in a band (that is, set the beat and tempo for a group of musicians performing the music)? Or is some pacemaking an emergent property of a seemingly uncoordinated group of cells getting together and jamming (thus there being no real ‘pacemaker’ but rather synchronicity across players emerging from the summation of asynchronous performances)? This special issue of The Journal of Physiology consists of a collection of invited topical reviews from experts in the field of pacemaking across a diverse range of cell types and physiological systems, including the heart, nervous system, gastrointestinal (GI) and urinary systems, male and female reproductive tracts, exocrine organs such as the pancreas and salivary glands and the kidneys and lymphatics. This is timely as the field of pacemaking and rhythmicity continues to evolve at a rapid pace, due to recent advances in optogenetics and cell-specific genetic manipulation, which are making monitoring and targeting of specific pacemaker cell populations within intact tissues possible. The special issue opens with a general review for the non-expert on one of the most studied and simultaneously most vigorously contested areas of pacemaking in physiology: the origin of cardiac automaticity in the sino-atrial node (SAN) of the heart. MacDonald and Quinn (2026) explain how the regular heartbeat, so vital to life, requires a redundant and robust pacemaker system, originating in cells of the SAN that provide rhythmic excitation to contracting cardiomyocytes. The paper describes a series of what have traditionally been termed ‘clocks’, proposed to explain the mechanisms by which regular SAN excitation comes about, with the ‘membrane clock’ (excitation driven by activation of transmembrane currents in SAN cells) and ‘calcium (Ca2+) clock’ (intracellular Ca2+ cycling) being the two most historically contested explanations for the origin of cardiac pacemaker activity. The authors also explain that a third clock – the ‘mechanics clock’ driven by the heart's exquisite mechano-sensitivity (Quinn & Kohl, 2021) – may be key to cardiac rhythmicity (Macdonald & Quinn, 2021). Ultimately the authors purport a more holistic view, by which the combined actions of these multiple, simultaneously acting systems act as ‘mutually entrained oscillators’ (rather than individual clocks) to generate the heartbeat. From this initial article a theme emerges that permeates other papers in the special issue: limitations on our ability to accurately identify cells as ‘specialised’ pacemakers. In particular, issues related to cellular markers for labelling specific subpopulations of cells as pacemakers within heterogenous tissues are a key point in multiple articles. In this vein, and staying with the heart, the next article from Saponaro and DiFrancesco (2026) summarises recent advances in our understanding of hyperpolarisation-activated cyclic nucleotide-gated (HCN) ion channel structure, the protein responsible for the ‘funny’ current, one of the key pacemaker currents in SAN cells. The paper describes how the recently resolved structure of HCN4 channels using cryogenic electron microscopy has helped us to understand the characteristics of the ‘funny’ current previously thought to be peculiar, by revealing how their form dictates their function. The special issue then moves on from the heart and into a comprehensive review of pacemaking in neurons in the brain. Bean (2026) describes commonalities between neuronal and cardiac pacemaking, in that populations of neurons are capable of spontaneous phasic activity without any sensory or synaptic input, driving rhythmic activity through generation of depolarising currents transduced to other cells, although highlighting that the ionic pacemaking apparatus in neurons is significantly different from cardiac cells. Ultimately this paper maps out a schematic of an ‘engine’ of neuronal pacemaking, centred on persistent, steady-state subthreshold sodium current, held in check from overexcitability by outward currents in non-pacemaking neuronal cells. Next, Sanders et al. (2026) describe the pacemaker cells of the GI tract: interstitial cells of Cajal (ICC). ICC are non-contractile cells that form interconnected networks between layers of smooth muscle cells. ICC generate and propagate slow waves of depolarising pacemaker events and transduce these signals to electrically connected smooth muscle cells in the GI tract via gap junctions. This enables co-ordinated rhythmic contractions of GI smooth muscle cells underlying motility patterns such as peristalsis, segmentation and propulsion. The article outlines the mechanistic underpinnings of GI pacemaking, highlighting key evidence supporting the concept of ICC as pacemaker cells. This description includes the importance of two key ionic conductances for the generation and propagation of slow waves in ICC not found in the smooth muscle cells – the Ca2+-activated chloride channel anoctamin-1 (ANO1) and the voltage-dependent Ca2+ channel Cav3.2 – and how Ca2+ release from intracellular stores in ICC couples to ANO1, leading to depolarisation and entrainment of Cav3.2, resulting in initiation of slow waves. This process is followed by sustenance of the plateau phase via temporal clustering of Ca2+ release, which further activates ANO1, followed by termination of the release of Ca2+ as intracellular stores are depleted and the Ca2+ release channels become refractory. The next paper examines the cellular identity of pacemakers of the lymphatic system, in which phasic contractions of lymphatic vessels are critical for lymph propulsion. Davis and Zawieja (2026) describe how the pacemaking frequency of lymphatic vessels – like the SAN of the heart (Quinn & Kohl, 2012) – is exquisitely mechanosensitive, and how lymphatic pacemaking is similar to that in the GI tract, relying on intracellular Ca2+ release (via inositol 1,4,5-trisphosphate receptor type 1) coupled to ANO1 to provide the excitatory depolarisation needed to activate voltage-dependent Cav1.2 channels and co-ordinated contraction of lymphatic smooth muscle cells. This concept is supported by a summary of emerging evidence using cell-specific reporters and knockout animals, which reveals how, in contrast to the GI tract, pacemaking in lymphatic vessels is an intrinsic property of the smooth muscle cells and thus myogenic in origin, not requiring a specialised cell type as in other organs. To this point, the special issue has focused on tissues and cells in the heart, brain, GI tract and lymphatic system, where pacemaking involves a ‘classical’ electrical mechanism, in which excitatory rhythmic depolarisations of one cell type are electrically communicated to other cell populations. Shifting to the exocrine system, Yule and Takano (2026) provide insight into a different, non-electrical model of pacemaking occurring in cells of the pancreas and salivary glands. In these tissues, intracellular Ca2+ mobilisation in specialised pancreatic acinar cells drives rhythmic fluid secretion and protein exocytosis, which spreads to adjacent cells via gap junctions. The authors outline the similarities of this concept of non-electrical pacemaking with pacemaking in the heart and GI tract, although highlighting that it occurs via a non-electrical mechanism, providing a hypothesis and evidence for how this takes place via intercellular diffusion of second messengers (such as inositol 1,4,5-trisphosphate and Ca2+) to elicit Ca2+ release in adjacent cells. Transitioning to the urinary tract, Drumm et al. (2026) describe the cellular origins and ionic conductances required for rhythmic muscle contraction in the bladder and urethra. In the urethra, the authors outline how spontaneous asynchronous rhythmic activity of urethral smooth muscle cells and bundles leads to sustained tonic contractions of the whole tissue, facilitating the role of the urethra as a sphincter to maintain continence as the bladder fills. The authors postulate a model in which summation of asynchronous phasic activity at the level of individual cells and muscle bundles generates a uniform urethral myogenic tone. The bladder is also described as exhibiting spontaneous phasic action potentials, Ca2+ signals and contractile activity, with the authors outlining the responsible cell types and conductances. The importance of species differences in pacemaker cell identity and function in the urinary tract is also discussed, although their exploration has been limited by a lack of effective markers for distinguishing specific cell populations. For instance ICC-like urethral interstitial cells may act as electrical pacemakers driving smooth muscle activity in rabbits, whereas spontaneously active ICC-like cells in mice appear not to act as electrical pacemakers, as adjacent cells are activated through non-electrical means. The authors also suggest that evidence for specialised pacemaking cells in the bladder is lacking but that a population of cells expressing platelet-derived growth factor receptor α (PDGFR-α) may serve as a ‘negative pacemaker’ by dampening the activity of electrically connected detrusor smooth muscle cells via activation of outward, repolarising currents. The theme of pacemaker cell ambiguity in complex multicellular systems is continued in the next review by Grainger (2026), who provides an overview of how mouse models with cell-specific fluorescent reporters have advanced our understanding of pacemaking in the renal pelvis of the upper urinary tract. The article describes how regular peristaltic contractions of the renal pelvis originate from a defined region at the pelvic–kidney junction and propagate distally, facilitating movement of urine from the kidney to the ureters. This description includes a historical summary of investigations exploring this pacemaker region and the cells that initiate its activity, and how recent experiments using optogenetic reporters and fluorescent markers have identified a population of PDGFR-α+ cells and atypical smooth muscle cells in the pelvic–kidney junction that express ANO1, which are spontaneously active and elicit depolarisations that may entrain voltage-dependent Ca2+ channels in adjoining smooth muscle cells. Using this evidence a model is proposed in which PDGFR-α+ cells in the renal pelvis condition the membrane potential of connected smooth muscle cells by asynchronous firing of depolarising events, thus increasing the probability of their activation and making pacemaking in the renal pelvis an emergent property of an interconnected syncytium. This is contrasted with other organ systems, in which an electrical pacemaker signal leads to a direct, one-for-one response in adjacent cells. Specialised PDGFR-α+ cells are also featured as potential pacemaker cells in the review by Hashitani et al. (2026), which focuses on the origins of pacemaking in the male reproductive organs. Based on technological advances in cell-specific markers and imaging approaches, it is proposed that subepithelial PDGFR-α+ cells expressing ANO1 drive spontaneous phasic contractions in the seminal vesicle and regions of the epididymis. Importantly it is highlighted that this pacemaking activity may occur through distinct cellular mechanisms in different regions of the same tissue. The authors outline two oscillator models in the epididymis: a cytosolic Ca2+ oscillator in the cauda region and a membrane oscillator in the proximal epididymis. The cytosolic Ca2+ oscillator bears similarities to pacemaker mechanisms for other organ systems described in the special issue, with intracellular Ca2+ release activating a Ca2+-activated chloride channel (possibly ANO1), which then activates voltage-dependent Ca2+ channels to trigger excitation–contraction coupling of smooth muscle cells. Conversely, pacemaking in the proximal epididymis does not rely on Ca2+ stores; instead pacemaker currents (that are still to be identified) depolarise cells to action potential threshold. The following article by Wray and Taggart (2026) details pacemaking in the female reproductive tract. Similar to other papers in the special issue, the authors highlight how investigations into the generation and co-ordination of rhythmicity in the female myometrium have been hampered by limitations in the experimental identification of specific pacemaker cell populations. Ultimately the authors conclude that – at least in human myometrium – there is no fixed pacemaker cell or pacemaker region but rather spatially transient initiation sites of spontaneous activity. Regular phasic contractions of myometrium thus do not require a fixed pacemaker, with co-ordinated activity instead emerging from seemingly discrete areas of uncoupled activity, similar to the emerging pacemaker phenomenon proposed for other organs. The final paper in the special issue from Xiong and Garfinkel (2026) asks a pointed question: ‘are physiological oscillations physiological?’ Their prospective comments indicate the fact that many homeostatic processes in physiology are the result of oscillatory behaviours, for instance, cyclical increases and decreases in glucose levels that regulate insulin secretion, oscillating concentrations of enzymes required for glycolysis, maintenance of circadian rhythms and the keeping of biological time. The review calls on readers to recognise that homeostasis is perhaps not achieved only by negative feedback bringing systems back to equilibrium setpoints but that more dynamic homeostatic paradigms exist, involving stable oscillatory patterns. The authors argue that an oscillatory-based model for physiological homeostasis provides built-in controls that protect systems from desensitisation and avoid chronic elevations of harmful byproducts, and that the use of non-linear dynamic mathematics may enable investigators to identify novel oscillatory behaviours in cells and tissues. Overall, the collection of papers in the special issue highlights the critical role that pacemaking plays in complex, multicellular organ systems across the body, while providing an overview of our current mechanistic understanding of pacemaker function, ultimately offering a valuable perspective on the gaps in our knowledge and opportunities for further research in the field. We would like to thank all the contributing authors for their thorough and timely work and hope this issue will inspire future discoveries to help determine who exactly is setting the pace. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. B.T.D. and T.A.Q. wrote the paper and agree to be accountable for all aspects of the work in ensuring that questions related to any part of its accuracy or integrity are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. This work was funded by the Irish Higher Education Authority Technological University Transformation Fund TUTFY2144 (to B.T.D.), the Canadian Institutes of Health Research (PJT-190009 to T.A.Q.), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2022-03150 to T.A.Q.) and the Heart and Stroke Foundation of Canada (G-22-0032127 to T.A.Q.).