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Cytosolic Ca²⁺ Buffers Are Inherently Ca²⁺ Signal Modulators.

ABSTRACT: For precisely regulating intracellular Ca²⁺ signals in a time- and space-dependent manner, cells make use of various components of the "Ca²⁺ signaling toolkit," including Ca²⁺ entry and Ca²⁺ extrusion systems. A class of cytosolic Ca²⁺-binding proteins termed Ca²⁺ buffers serves as modulators of such, mostly short-lived Ca²⁺ signals. Prototypical Ca²⁺ buffers include parvalbumins (α and β isoforms), calbindin-D9k, calbindin-D28k, and calretinin. Although initially considered to function as pure Ca²⁺ buffers, that is, as intracellular Ca²⁺ signal modulators controlling the shape (amplitude, decay, spread) of Ca²⁺ signals, evidence has accumulated that calbindin-D28k and calretinin have additional Ca²⁺ sensor functions. These other functions are brought about by direct interactions with target proteins, thereby modulating their targets' function/activity. Dysregulation of Ca²⁺ buffer expression is associated with several neurologic/neurodevelopmental disorders including autism spectrum disorder (ASD) and schizophrenia. In some cases, the presence of these proteins is presumed to confer a neuroprotective effect, as evidenced in animal models of Parkinson's or Alzheimer's disease.

SUBMITTER: Schwaller B

PROVIDER: S-EPMC6942125 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Mucociliary clearance is a pivotal physiological mechanism that protects the lung by cleaning the airways from pollution and colonization, thereby preventing infection. Ciliary function is influenced by various signal transduction cascades, and Ca2+ represents a key second messenger. A fixed 20:1 combination of cafedrine and theodrenaline has been widely used to treat perioperative hypotension and emergency hypotensive states since the 1960s; however, its effect on the intracellular Ca2+ concentration ([Ca2+]i) of respiratory epithelium remains unknown. Therefore, human tracheal epithelial cells were exposed to the clinically applied 20:1 mixture of cafedrine/theodrenaline and the individual substances separately. [Ca2+]i was assessed by FURA-2 340/380 fluorescence ratio. Pharmacological inhibitors were applied to elucidate relevant signal transduction cascades, and reverse transcription polymerase chain reaction (RT-PCR) was performed on murine tracheal epithelium to analyze ryanodine receptor (RyR) subtype expression. All three pharmacological preparations instantaneously induced a steep increase in [Ca2+]i that quickly returned to its baseline value despite the persistence of each substance. Peak [Ca2+]i following the administration of 20:1 cafedrine/theodrenaline, cafedrine alone, and theodrenaline alone increased in a dose-dependent manner, with median effective concentrations of 0.35 mM (7.32 mM cafedrine and 0.35 mM theodrenaline), 3.14 mM, and 3.45 mM, respectively. When extracellular Ca2+ influx was inhibited using a Ca2+-free buffer solution, the peak [Ca2+]i following the administration of cafedrine alone and theodrenaline alone were reduced but not abolished. No alteration in [Ca2+]i compared with baseline [Ca2+]i was observed during β-adrenergic receptor inhibition. Depletion of caffeine-sensitive stores and inhibition of RyR, but not IP3 receptors, completely abolished any increase in [Ca2+]i. However, [Ca2+]i still increased following the depletion of mitochondrial Ca2+ stores using 2,4-dinitrophenol. RT-PCR revealed RyR-2 and RyR-3 expression on murine tracheal epithelium. Although our experiments showed that cafedrine/theodrenaline, cafedrine alone, or theodrenaline alone release Ca2+ from intracellular stores through mechanisms that are exclusively triggered by β-adrenergic receptor stimulation, which most probably lead to RyR activation, clinical plasma concentrations are considerably lower than those used in our experiments to elicit an increase in [Ca2+]i; therefore, further studies are needed to evaluate the ability of cafedrine/theodrenaline to alter mucociliary clearance in clinical practice.

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Cytosolic Ca²⁺ Buffers Are Inherently Ca²⁺ Signal Modulators.

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Dataset Information

Cytosolic Ca2+ Buffers Are Inherently Ca2+ Signal Modulators.

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OmicsDI is part of the ELIXIR infrastructure

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Cytosolic Ca²⁺ Buffers Are Inherently Ca²⁺ Signal Modulators.