Assessing Different Temporal Scales of Calcium Dynamics in Networks of Beta Cell Populations

Abstract

Beta cells within the pancreatic islets of Langerhans respond to stimulation with coherent oscillations of membrane potential and intracellular calcium concentration that presumably drive the pulsatile exocytosis of insulin. Their rhythmic activity is multimodal, resulting from networked feedback interactions of various oscillatory subsystems, such as the glycolytic, mitochondrial, and electrical/calcium components. How these oscillatory modules interact and affect the collective cellular activity, which is a prerequisite for proper hormone release, is incompletely understood. In the present work, we combined advanced confocal Ca2+ imaging in fresh mouse pancreas tissue slices with time series analysis and network science approaches to unveil the glucose-dependent characteristics of different oscillatory components on both the intra- and inter-cellular level. Our results reveal an interrelationship between the metabolically driven low-frequency component and the electrically driven high-frequency component, with the latter exhibiting the highest bursting rates around the peaks of the slow component and the lowest around the nadirs. Moreover, the activity, as well as the average synchronicity of the fast component, considerably increased with increasing stimulatory glucose concentration, whereas the stimulation level did not affect any of these parameters in the slow component domain. Remarkably, in both dynamical components, the average correlation decreased similarly with intercellular distance, which implies that intercellular communication affects the synchronicity of both types of oscillations. To explore the intra-islet synchronization patterns in more detail, we constructed functional connectivity maps. The subsequent comparison of network characteristics of different oscillatory components showed more locally clustered and segregated networks of fast oscillatory activity, while the slow oscillations were more global, resulting in several long-range connections and a more cohesive structure. Besides the structural differences, we found a relatively weak relationship between the fast and slow network layer, which suggests that different synchronization mechanisms shape the collective cellular activity in islets, a finding which has to be kept in mind in future studies employing different oscillations for constructing networks.

Dual Mode of Action of Acetylcholine on Cytosolic Calcium Oscillations in Pancreatic Beta and Acinar Cells In Situ

“…increase Ca 2+ mobilization through modulation of the ryanodine receptors (RYRs Independently of IP3, the second messenger nicotinic acid adenine dinucleotide phate (NAADP) likewise acts on separate receptors to mobilize intracellular Ca 2+ [3 Oscillations in [Ca 2+ ]c are involved in the regulation of numerous cellular proc [41], including insulin secretion in beta cells [42]. [Ca 2+ ]c oscillations in beta cells found to be of very different time scales, and are thought to correspond to pulsatile in release [43][44][45][46]. Similarly, Ca 2+ signaling plays a prominent role for the digestive en Oscillations in [Ca 2+ ] c are involved in the regulation of numerous cellular processes [41], including insulin secretion in beta cells [42].…”

“…Similarly, Ca 2+ signaling plays a prominent role for the digestive en Oscillations in [Ca 2+ ] c are involved in the regulation of numerous cellular processes [41], including insulin secretion in beta cells [42]. [Ca 2+ ] c oscillations in beta cells were found to be of very different time scales, and are thought to correspond to pulsatile insulin release [43][44][45][46]. Similarly, Ca 2+ signaling plays a prominent role for the digestive enzyme secretion in acinar cells [47,48].…”

The New Field of Network Physiology: Building the Human Physiolome

“…New computational and analytical approaches are needed to extract information from complex data, to infer transient interactions between dynamically changing systems, and to quantify global behavior at the organism level generated by networks of interactions that are function of time. In fact, in recent years, we have already witnessed the broad impact of introducing novel concepts and methods derived from modern statistical physics and network theory to biology and medicine, shifting the paradigm from reductionism to a new integrative framework essential to address fundamentally new problems in systems biology (Yao et al, 2019;Prats-Puig et al, 2020;Corkey and Deeney, 2020;Rizi et al, 2021;Barajas-Martínez et al, 2020), neuroscience (Castelluzzo et al, 2020;Pa¨eske et al, 2020;Fesce, 2020;Stramaglia et al, 2021), physiology (Podobnik et al, 2020;Zmazek et al, 2021), clinical medicine (Loscalzo and Barabasi, 2011;Delussi et al, 2020;Li et al, 2020;Liu et al, 2020;McNorgan et al, 2020;Tan et al, 2020;Haug et al, 2021;Liu et al, 2021) and even drug discovery (Hopkins, 2008). A central focus of research within this integrative framework is the interplay between structural connectivity and functional dependency, a key problem in neuroscience, brain research (Bullmore and Sporns, 2009;Gallos et al, 2012;Rothkegel and Lehnertz, 2014;Liu et al, 2015a;Bolton et al, 2020;Wang and Liu, 2020) and human physiology (Pereira-Ferrero et al, 2019;Lavanga et al, 2020;Barajas-Martínez et al, 2021;Gao et al, 2018;Balagué et al, 2020;Porta et al, 2017;Lioi et al, ...…”

The Role of cAMP in Beta Cell Stimulus–Secretion and Intercellular Coupling

“…For beta cells, intercellular coupling established through gap junctions composed of Cx36 is particularly important, as it provides the necessary and the most important substrate for coordinated responses of the beta cell population, a prerequisite for the well-regulated secretion of insulin [ 57 , 62 , 72 ]. Specifically, gap junctions are a type of specialized membrane contacts that enable direct communication by allowing current-carrying ions and other small molecules to pass directly into the cytoplasm of adjacent cells, giving rise to propagating intercellular waves [ 5 , 55 , 56 , 57 , 58 , 169 , 170 , 171 , 172 , 173 ] [ 70 , 174 , 175 , 176 , 177 , 178 ]. Cx36 gap junction channels are size- and charge-selective and favor the exchange of positively charged molecules at the expense of anionic molecules [ 179 , 180 ].…”