Acid Sphingomyelinase Impacts Canonical Transient Receptor Potential Channels 6 (TRPC6) Activity in Primary Neuronal Systems

Abstract

The acid sphingomyelinase (ASM)/ceramide system exhibits a crucial role in the pathology of major depressive disorder (MDD). ASM hydrolyzes the abundant membrane lipid sphingomyelin to ceramide that regulates the clustering of membrane proteins via microdomain and lipid raft organization. Several commonly used antidepressants, such as fluoxetine, rely on the functional inhibition of ASM in terms of their antidepressive pharmacological effects. Transient receptor potential canonical 6 (TRPC6) ion channels are located in the plasma membrane of neurons and serve as receptors for hyperforin, a phytochemical constituent of the antidepressive herbal remedy St. John’s wort. TRPC6 channels are involved in the regulation of neuronal plasticity, which likely contributes to their antidepressant effect. In this work, we investigated the impact of reduced ASM activity on the TRPC6 function in neurons. A lipidomic analysis of cortical brain tissue of ASM deficient mice revealed a decrease in ceramide/sphingomyelin molar ratio and an increase in sphingosine. In neurons with ASM deletion, hyperforin-mediated Ca2+-influx via TRPC6 was decreased. Consequently, downstream activation of nuclear phospho-cAMP response element-binding protein (pCREB) was changed, a transcriptional factor involved in neuronal plasticity. Our study underlines the importance of balanced ASM activity, as well as sphingolipidome composition for optimal TRPC6 function. A better understanding of the interaction of the ASM/ceramide and TRPC6 systems could help to draw conclusions about the pathology of MDD.

Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke

“…TRPC6 is expressed in many different brain regions, such as the cortex, hippocampus, cerebellum, basal ganglia, thalamus, hypothalamus, and dorsal root ganglia [ 57 ]. Numerous studies have documented that the expression of TRPC6 in primary cultured neurons or neuronal cell lines is protective under various stress conditions [ 48 , 58 , 59 , 60 , 61 , 62 ].…”

The Multiple Roles of Sphingomyelin in Parkinson’s Disease

“…It is known that the aSMase/Cer balance is altered in chronic stress and major depressive disorder characterized by mood changes, somatic alterations, and often suicide. Therefore, aSMase was studied as a target in the preparation of several commonly used antidepressants [ 46 ]. This is relevant considering that aSMase interacts with transient receptor potential canonical 6 ion channels located in the plasma membrane of neurons that act as receptors for antidepressive herbal remedies, i.e., hyperforin [ 46 ].…”

“…Therefore, aSMase was studied as a target in the preparation of several commonly used antidepressants [ 46 ]. This is relevant considering that aSMase interacts with transient receptor potential canonical 6 ion channels located in the plasma membrane of neurons that act as receptors for antidepressive herbal remedies, i.e., hyperforin [ 46 ]. Antidepressant drugs such as amitriptyline and fluoxetine stimulate SM accumulation in lysosomes and Golgi membranes, which are responsible for autophagy of hippocampal neurons, by inhibiting aSMas.…”

New Molecular Targets for Antidepressant Drugs

“…Hyperforin, a component of St. John’s wort used to treat mild to moderate depression [ 48 ] activates TRPC6 channels. The inhibition of ASM reduces ceramide abundance in the cell membrane, preventing clustering of TRPC6 in lipid rafts and thus altering TRPC6 function [ 49 ].…”