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Review
. 2021 Nov 20:765:136258.
doi: 10.1016/j.neulet.2021.136258. Epub 2021 Sep 22.

Role of TRP ion channels in cerebral circulation and neurovascular communication

Maniselvan Kuppusamy  1 , Matteo Ottolini  2 , Swapnil K Sonkusare  3
Affiliations
Review

Role of TRP ion channels in cerebral circulation and neurovascular communication

Maniselvan Kuppusamy et al. Neurosci Lett. .

Abstract

The dynamic regulation of blood flow is essential for meeting the high metabolic demands of the brain and maintaining brain function. Cerebral blood flow is regulated primarily by 1) the intrinsic mechanisms that determine vascular contractility and 2) signals from neurons and astrocytes that alter vascular contractility. Stimuli from neurons and astrocytes can also initiate a signaling cascade in the brain capillary endothelium to increase regional blood flow. Recent studies provide evidence that TRP channels in endothelial cells, smooth muscle cells, neurons, astrocytes, and perivascular nerves control cerebrovascular contractility and cerebral blood flow. TRP channels exert their functional effects either through cell membrane depolarization or by serving as a Ca2+ influx pathway. Endothelial cells and astrocytes also maintain the integrity of the blood-brain barrier. Both endothelial cells and astrocytes express TRP channels, and an increase in endothelial TRP channel activity has been linked with a disrupted endothelial barrier function. Therefore, TRP channels can play a potentially important role in regulating blood-brain barrier integrity. Here, we review the regulation of cerebrovascular contractility by TRP channels under healthy and disease conditions and their potential roles in maintaining blood-brain barrier function.

Keywords: Blood-brain barrier; Cerebral blood flow; Cerebral microcirculation; Neurovascular coupling; TRP channels.

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Figures

Figure 1:
Figure 1:. TRP channels regulate pial arterial contractility.
Endothelial Cells: Ca2+ influx through TRPV3, TRPV4, and TRPA1 channels activates nearby intermediate (IK) and small (SK) conductance Ca2+-activated potassium channels, causing vasodilation. TRPM2 channels are another Ca2+ entry pathway in cerebral endothelial cells. Smooth muscle cells: Ca2+ influx through plasma membrane TRPV4 channels or Ca2+ release through late endo-lysosome (LEL) TRPML1 channel activates ryanodine receptors (RyR), resulting in Ca2+ release (Ca2+ Sparks) from the sarcoplasmic reticulum (SR). Ca2+ sparks, in turn, stimulate large-conductance Ca2+-activated potassium (BK) channels, leading to SMC relaxation and vasodilation. Ca2+ entry through TRPC6, TRPC3, and TRPP1 channels triggers Ca2+ release from the SR via IP3 receptors (IP3R). IP3R Ca2+ signals activate sodium influx through TRPM4 channels, leading to SMC depolarization and vasoconstriction. Perivascular Sensory Nerves: Ca2+ entry via TRPA1 and TRPV1 channels induces the release of CGRP (calcitonin gene-ralated peptide) and vasodilation.
Figure 2:
Figure 2:. TRP channel regulation of parenchymal arteriolar contractility.
Endothelial Cells: Ca2+ influx through TRPV3, TRPV4, and TRPA1 channels activates nearby intermediate (IK) and small (SK) conductance Ca2+-activated potassium channels, causing vasodilation. Smooth muscle cells: Ca2+ entry through TRPC6 channels stimulates Ca2+ release from the sarcoplasmic reticulum (SR) via inositol triphosphate receptors (IP3R). IP3R-mediated Ca2+ release activates sodium currents through TRPM4 channels, depolarizing the SMC membrane and causing vasoconstriction. Ca2+ influx through TRPV4 channels stimulates Ca2+ release from the SR through ryanodine receptors (RyR) and activates large-conductance Ca2+-activated potassium channels (BK), leading to SMC hyperpolarization and vasodilation. Astrocytic Endfeet: Ca2+ signals through TRPV4 channels are amplified by Ca2+-induced Ca2+ release via IP3Rs. This mechanism increases boosts neurovascular coupling and dilates parenchymal arterioles. TRPC6 channel is another essential regulator of astrocytic Ca2+ homeostasis.
Figure 3:
Figure 3:. TRP channel regulation of neurovascular communication at the level of capillaries.
Ca2+ influx through TRPV4 channels is promoted by Gq protein-coupled receptor (GqPCR) signaling in the capillary endothelium. Activation of phospholipase C by Gq proteins lowers phosphatidylinositol 4,5-bisphosphate (PIP2) levels. PIP2 inhibits TRPV4 channels and activates inwardly rectifying potassium (Kir) channels. Thus, GqPCR signaling disinhibits TRPV4 channels and lowers the activity of Kir channels. Ca2+ influx signals through TRPA1 channels stimulate nearby Pannexin 1 channels, promoting ATP release. ATP activates Ca2+-permeable purinergic P2X receptor ion channels. The capillary Ca2+ events propagate upstream to the parenchymal arteriolar endothelium resulting in vasodilation. The role of TRP channels in pericytes is largely unknown.
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