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  • br Discussion RBCs possess a much simpler composition


    Discussion RBCs possess a much simpler composition and structure than other eukaryotic pitavastatin and can therefore serve as a convenient system on which to study how cell functioning relates to the molecular and supramolecular properties of its constituents. The model developed in this work is aimed at explaining the contribution of the mechanosensitive protein Piezo1 to the regulation of RBC volume. It brings together several previous studies on RBC osmotic properties (3, 39), the shape behavior of vesicles and RBCs (32), the curvature dependence of the lateral distribution of membrane inclusions (34, 35, 36, 40) and consequent curvature-dependent mechanosensitivity (33), and on the relationships between the variability parameters of RBC properties (41, 42, 43). We first comment on the model’s principal constituents, then discuss its outcomes and limitations, finally suggesting its possible extensions and proposing some experimental verifications.
    Author Contributions
    The study was supported by the Slovenian Research Agency through grant P1-0055.
    Introduction Since the seminal work demonstrating that endocrine cells of the anterior pituitary gland generate calcium-dependent action potentials more than 40 years ago (Kidokoro, 1975) our understanding of how this electrical activity is shaped and the role of different patterns of excitability in coordinating hormone secretion in pituitary cells has undergone a dramatic transformation (Mason et al., 1988, Mollard and Schlegel, 1996, Ozawa and Sand, 1986, Stojilkovic, 2006, Stojilkovic et al., 2010). Important in this context is that endocrine pituitary cells exploit an eclectic array of ion channels, signaling pathways and mechanisms to control patterns of excitability in a cell specific manner dependent upon the ionic makeup of endocrine pituitary cell types. Moreover, while anterior pituitary cells exploit actions potentials they are not simply neurons or skeletal muscles in disguise – the classical electrically excitable cells. Rather, interrogation of anterior pituitary endocrine excitability has provided seminal insights into the mechanisms of ion channel regulation and endocrine stimulus-secretion coupling and how unique and diverse ionic mechanisms can be exploited by excitable cells to allow context- and cell-specific regulation. Nowhere is the extraordinary diversity of mechanism, properties and physiological function of pituitary cell excitability been more evident than in studies that have revealed novel, and often paradoxical, roles of the family of calcium-activated potassium channels. This channel family, that comprises three different gene families whose members have distinct properties (Fig. 1), regulation and function (Kaczmarek et al., 2017), are activated by elevations in intracellular free calcium resulting from influx of calcium from the extracellular space or resulting from release from intracellular calcium stores (Fig. 2). Conceptually, activation of a calcium-activated potassium channel and subsequent efflux of potassium ions might simply be assumed to result in membrane repolarization and hyperpolarization and thus dampen endocrine pituitary excitability. While this is the ‘classical’ case in many systems, what is now evident, is that calcium-activated potassium channels play very diverse and surprising roles that provide mechanisms to allow cell-specific and context specific control of anterior pituitary endocrine cell excitability.
    A brief primer on calcium-activated potassium channels Since the initial discovery that intracellular free calcium can activate potassium selective conductances in red blood cells almost 60 years ago (Gardos, 1958) three distinct families of calcium-activated potassium channels have been identified (Fig. 1) that differ in their properties, mode of regulation by calcium, tissue expression, pharmacology and physiological function (Kaczmarek et al., 2017). Importantly, dysfunction of calcium-activated potassium channels in humans and animals is associated with an eclectic array of diseases ranging from cancers to neurological, metabolic, endocrine and vascular disorders (for reviews see Adelman et al., 2012, Christophersen and Wulff, 2015, Contreras et al., 2013, Köhler et al., 2016, Latorre et al., 2017, Stocker, 2004). All three families have been reported to control anterior pituitary cell excitability however, their functional role displays considerable cell and context specificity and the extent to which their dysfunction in the pituitary may contribute to human and animal disease is largely unexplored.