Interactions of the Mechanosensitive Channels with Extracellular Matrix, Integrins, and Cytoskeletal Network in Osmosensation

Abstract

Life is maintained in a sea water-like internal environment. The homeostasis of this environment is dependent on osmosensory system translation of hydromineral information into osmotic regulatory machinery at system, tissue and cell levels. In the osmosensation, hydromineral information can be converted into cellular reactions through osmoreceptors, which changes thirst and drinking, secretion of antidiuretic vasopressin (VP), reabsorption of water and salt in the kidneys at systemic level as well as cellular metabolic activity and survival status at tissue level. The key feature of osmosensation is the activation of mechanoreceptors or mechanosensors, particularly transient receptor potential vallinoid (TRPV) and canonical (TRPC) family channels, which increases cytosolic Ca²⁺ levels, activates osmosensory cells including VP neurons and triggers a series of secondary reactions. TRPV channels are sensitive to both hyperosmotic and hyposmotic stimuli while TRPC channels are more sensitive to hyposmotic challenge in neurons. The activation of TRP channels relies on changes in cell volume, membrane stretch and cytoskeletal reorganization as well as hydration status of extracellular matrix (ECM) and activity of integrins. Different families of TRP channels could be activated differently in response to hyperosmotic and hyposmotic stimuli in different spatiotemporal orders, leading to differential reactions of osmosensory cells. Together, they constitute the osmosensory machinery. The activation of this osmoreceptor complex is also associated with the activity of other osmolarity-regulating organelles, such as water channel protein aquaporins, Na-K-2Cl cotransporters, volume-sensitive anion channels, sodium pump and purinergic receptors in addition to intercellular interactions, typically astrocytic neuronal interactions. In this article, we review our current understandings of the composition of osmoreceptors and the processes of osmosensation.

Keywords: cytoskeleton; extracellular matrix; integrin; transient receptor potential canonical channel; transient receptor potential vallinoid channel; vasopressin.

Figure 1

Schematic diagram of hypothetical osmoreceptors and osmosensation. (A) Composition of osmoreceptors and osmosensation at resting condition. Cation along with water binds with extracellular matrix (ECM) that interacts with integrins embedded in plasma membrane and spatially-conjugated with transient receptor potential (TRP) vallinoid (TRPV) and canonical (TRPC) family channels. The ECM-integrin-TRP channel complex could bind to microtubule network directly or through actin filaments. The integrins and cytoskeletal networks connected with TRPVs and TRPCs could be different, which would allow hyperosmotic cell shrinkage and hyposmotic swelling to activate the two families in different manners. (B) Hyperosmotic stimulus (stim.). (Ba) Initial cellular reactions. The ECM binding with cation and water activates TRPV-associated integrins and the ensuing conformational change of integrins leads to partial opening of TRPVs. However, the integrin subunits binding to TRPCs could be different from that to TRPVs and show no activation during cell shrinkage. (Bb) Cellular reactions toward full cell shrinkage. Hyperosmotic environment draws water outflow from intracellular compartment, decreases cell volume and increases the pushing force (black arrows) of cytoskeletal network for the full opening of TRPVs. (Bc) Regulatory volume increase (RVI) following full cell shrinkage. Activation of TRPVs triggers oscillatory cytosolic Ca²⁺ increase, activates mitogen-activated kinases, and installs more aquaporins on the membrane, thereby leading to a RVI, which could reduce microtubule-associated TRPV opening but cause partial opening of TRPCs through relative volemic increase that yields a pulling force between TRPCs and cytoskeletal network. As a result, hyperosmotic activation of osmosensory neurons occurs. (C) Hyposmotic stimulus. (Ca) Initial cellular reactions. Hyposmotic environment decreases the activity of integrins by uncoupling ECM with integrins but initiates cell swelling, leading to complete inhibition of TRPVs. The swelling and mild membrane tension causes partial activation of TRPCs, which could result from a pulling force (black arrows) of cytoskeletal network. At this stage, weakly increased cytosolic Ca²⁺ through TRPCs could activate K⁺ current and thus, inhibition of osmosensory neurons occurs. (Cb) Cellular reactions toward full cell swelling. As water increasingly gets into the cells and increases intracellular volume, increased interactions between ECM and TRPV-associated integrins cause activation of TRPVs while further activating TRPCs. As a result, reversal of hyposmotic inhibition occurs. (Cc) Regulatory volume decrease (RVD) following full cell swelling. As the swelling of cells proceeds, volume-/stretch-sensitive anion channels are also activated, which leads to RVD and volume reduction. Once the RVD occurs, interactions between microtubule networks and TRPVs also increase while opening of TRPCs is partially decreased. As a result, osmosensory neurons could show prolonged excitation or apoptotic alteration.