The Ion Channel and GPCR Toolkit of Brain Capillary Pericytes

Abstract

Brain pericytes reside on the abluminal surface of capillaries, and their processes cover ~90% of the length of the capillary bed. These cells were first described almost 150 years ago (Eberth, 1871; Rouget, 1873) and have been the subject of intense experimental scrutiny in recent years, but their physiological roles remain uncertain and little is known of the complement of signaling elements that they employ to carry out their functions. In this review, we synthesize functional data with single-cell RNAseq screens to explore the ion channel and G protein-coupled receptor (GPCR) toolkit of mesh and thin-strand pericytes of the brain, with the aim of providing a framework for deeper explorations of the molecular mechanisms that govern pericyte physiology. We argue that their complement of channels and receptors ideally positions capillary pericytes to play a central role in adapting blood flow to meet the challenge of satisfying neuronal energy requirements from deep within the capillary bed, by enabling dynamic regulation of their membrane potential to influence the electrical output of the cell. In particular, we outline how genetic and functional evidence suggest an important role for Gs-coupled GPCRs and ATP-sensitive potassium (KATP) channels in this context. We put forth a predictive model for long-range hyperpolarizing electrical signaling from pericytes to upstream arterioles, and detail the TRP and Ca2+ channels and Gq, Gi/o, and G12/13 signaling processes that counterbalance this. We underscore critical questions that need to be addressed to further advance our understanding of the signaling topology of capillary pericytes, and how this contributes to their physiological roles and their dysfunction in disease.

Distinct signatures of calcium activity in brain mural cells

“…Although phenotypic diversity of mural cells was already outlined in the earliest descriptions of pericytes almost a century ago (Zimmermann, 1923), there is still no consensus on mural cell classifications in the brain (Attwell et al, 2016). Especially mural cells located at the terminal end of arterioles (1 st -4 th branch order) are not clearly defined and were variously named in recent literature as precapillary/terminal SMCs (Hill et al, 2015), contractile mural cells (Hariharan et al, 2020), contractile pericytes (Gonzales et al, 2020) or ensheathing pericytes (Berthiaume et al, 2021). Whether these cells are a subtype of SMCs or pericytes remains to be elucidated.…”

“…Since expression of smooth muscle actin in CPs seems absent or very low (Grant et al, 2017, Alarcon-Martinez et al, 2018, the type of contractile machinery in CPs remains to be elucidated. Further knowledge of the pericyte calcium-signaling toolkit (Hariharan et al, 2020) may help to understand the consequences of altered calcium signaling in pericytes in physiological and pathophysiological conditions.…”

Transcriptomic Analysis of Human Brain -Microvascular Endothelial Cell Driven Changes in -Vascular Pericytes

“…Pericytes are the first cells to relax during neural activity, leading to capillary dilation and increased cerebral blood flow (CBF) to boost energy supply [ 72 ]. Since local ion concentrations substantially contribute to the establishment of resting and action potentials, thereby regulating cell excitability [ 73 , 74 ], the regulation of many ion channels and GPCRs in PCs co-cultured with ECs indicates that co-culture substantially influences the ability of PCs to regulate CBF. Pericyte membrane hyperpolarization has further been implicated to lead to long-range electrical signaling to vascular smooth muscle cells, which further impacts CBF [ 73 ].…”

Human Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells: Current Controversies

“…The major endothelial transport systems, ions channels and GPCRs are described in detail elsewhere ( Daneman and Prat, 2015 ; Vanlandewijck et al, 2018 ; Hariharan et al, 2020 ). The unique cellular junction molecules expressed by brain endothelial cells are briefly discussed below.…”