Primary Cilia and Calcium Signaling Interactions

Abstract

The calcium ion (Ca²⁺) is a diverse secondary messenger with a near-ubiquitous role in a vast array of cellular processes. Cilia are present on nearly every cell type in either a motile or non-motile form; motile cilia generate fluid flow needed for a variety of biological processes, such as left-right body patterning during development, while non-motile cilia serve as the signaling powerhouses of the cell, with vital singling receptors localized to their ciliary membranes. Much of the research currently available on Ca²⁺-dependent cellular actions and primary cilia are tissue-specific processes. However, basic stimuli-sensing pathways, such as mechanosensation, chemosensation, and electrical sensation (electrosensation), are complex processes entangled in many intersecting pathways; an overview of proposed functions involving cilia and Ca²⁺ interplay will be briefly summarized here. Next, we will focus on summarizing the evidence for their interactions in basic cellular activities, including the cell cycle, cell polarity and migration, neuronal pattering, glucose-mediated insulin secretion, biliary regulation, and bone formation. Literature investigating the role of cilia and Ca²⁺-dependent processes at a single-cellular level appears to be scarce, though overlapping signaling pathways imply that cilia and Ca²⁺ interact with each other on this level in widespread and varied ways on a perpetual basis. Vastly different cellular functions across many different cell types depend on context-specific Ca²⁺ and cilia interactions to trigger the correct physiological responses, and abnormalities in these interactions, whether at the tissue or the single-cell level, can result in diseases known as ciliopathies; due to their clinical relevance, pathological alterations of cilia function and Ca²⁺ signaling will also be briefly touched upon throughout this review.

Keywords: calcium signaling; chemosensation; fluid shear; mechanosensation; primary cilia.

Figure 1

Primary cilia structure. The axonemes of primary cilia are anchored on the basal body and encapsulated within the ciliary membrane. The ciliary membrane is one continuous extension of the plasma membrane. The basal body is composed of the mother and the daughter centrioles, as well as some transition fibers that anchor the basal body to the cell membrane. The ciliary membrane houses specific membrane and protein receptors, all of which facilitate proper cilia signaling (left panel). Primary cilia that are found on vascular endothelial cells are identifiable by an immunofluorescence technique with antibody against acetylated α-tubulin (green) labeling primary cilia, and pericentrin (red) labeling the centriole or basal body. The nucleus is counterstained with DAPI (blue) to label DNA (right panel). Left panel is adopted with permission from ref. [27].

Figure 2

Primary cilia activation by fluid shear stress and nitric oxide (NO) signaling in the vascular endothelia. Left panel: Primary cilia bending in response to fluid flow-generated shear stress. Subsequent biosynthesis of and release of nitric oxide (NO) is also shown. Right Panel: The production and release of NO occurs due to activation of primary cilia within endothelial vasculature. When cilia experience shear stress, the mechanosensory polycystin complex activates, which initiates the synthesis and release of NO. The resultant biochemical cascade involves an extracellular calcium (Ca²⁺) influx, followed by the activation of multiple Ca²⁺-dependent proteins, including calmodulin (CaM), protein kinase C (PKC), and AKT/PKB, which in turn trigger endothelial nitric oxide synthase (eNOS), and NO is produced and released. Figure is adopted with permission from ref. [30].