S1P/S1P Receptor Signaling in Neuromuscolar Disorders

Abstract

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot-Marie-Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy.

Keywords: Charcot-Marie-Tooth disease; ceramide; duchenne muscular dystrophy; myasthenia gravis; nervous system; neuromuscular disease; skeletal muscle; sphingolipids; sphingosine 1-phosphate receptors.

Figure 1

S1P receptor-activated pathways and intracellular targets of S1P. S1P is synthesized from sphingosine (Sph) by the sphingosine kinase isoforms SphK1 and SphK2, and it is irreversibly cleaved by S1P lyase (SPL), or dephosphorylated by S1P phosphatases (SPP) localized mainly in the endoplasmic reticulum and also in the nucleus. S1P produced inside the cell can be transported to the intercellular space by an S1P transporter. As a ligand, S1P acts as autocrine and paracrine factor triggering specific signaling pathways by interacting with S1P specific heterotrimeric GTP binding protein-coupled receptors (S1PRs). S1PR activation modulates extracellular signal–regulated kinases (ERK), Rho and Rac GTPases, phospholipase C (PLC), and phosphoinositide 3-kinases (PI3K) and, in turn, multiple signaling pathways. Subcellular localization of S1P intracellular targets is indicated: cytoplasm for atypical protein kinase C (aPKCs), tumor necrosis factor receptor-associated factor 2 (TRAF-2), mitochondria for prohibitin 2 (PHB2), dynamin-related protein 1 (Drp1), mitofusin 2 (Mfn2), optic atrophy 1 (Opa1), nucleus for histone deacetylases (HDACs), telomerase (TerT), and poly (ADP-ribose) polymerases (PARP). Moreover, S1P specifically interacts with the N-terminal domain of the heat shock proteins GRP94 and HSP90αγ.

Figure 2

Sphingolipid metabolism and S1P/S1P receptors signaling and summary of the metabolic pathways associated with neuromuscular diseases. Disease names in light red are linked to defects in the sphingolipid metabolism /S1P/S1PR signaling. Ceramide (Cer) is formed via the sphingomyelin (SM) cycle or de novo sphingolipid synthesis involving serine palmitoyl transferase (SPT), 3-keto reductase (3KR), ceramide synthase (CerS), and desaturase (DES), and converted reversibly to sphingosine (Sph) by ceramidase (CDase), or phosphorylated to ceramide-1-phosphate (C1P) by ceramide kinase (CerK) activity. S1P is synthesized from sphingosine (Sph) by the sphingosine kinases and irreversible cleaved by S1P lyase (S1PL), which generates hexadecenal and phosphoethanolamine. S1P is also a substrate of specific S1P phosphatases (SPPase). S1P produced inside the cell can be transported in the intercellular space by an ATP-binding cassette transporter named spinster homolog 2 (Spns2). As a ligand, S1P acts as autocrine and paracrine factor triggering specific signaling pathways by interacting with S1P specific heterotrimeric GTP binding protein-coupled receptors, named S1PR. After ligand binding, the G protein α subunit (Gαs, Gαi, Gαq, Gα12/13), together with the bound GTP, dissociates from the β γ complex and they affect intracellular signaling proteins or target functional proteins directly. Five subtypes of S1PRs have been described and appear to be selectively expressed in skeletal muscle cells and the nervous system. Other abbreviations: SMase, sphingomyelinase; ALS, amyotrophic lateral sclerosis; CMT, Charcot–Marie–Tooth disease; DMD, Duchenne muscular dystrophy; GCS, glucosylceramide synthase; MG, myastenia gravis; MS, multiple sclerosis [29]; SMS, sphingomyelin synthase; SPT, serine palmitoyltransferase. The signalling pathways downstream to each specific S1P receptor subtype are drawn as arrows of the same color of the S1P receptor