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Charcot‑Marie‑Tooth type 1A (CMT1A) is a dysmyelinating disease of the peripheral nervous system that results in a slow progressive weakening and wasting of the distal muscles of the upper and lower limbs. Despite extensive research and clinical trials there is still no treatment for CMT1A that results in complete neurological improvement. Recent studies investigating various pharmacological modulators of adenylyl cyclase activity, including ascorbic acid and ligands of G protein‑coupled receptors (GPCRs), provide hope for future treatments of this type of hereditary motor and sensory neuropathy. A review of mechanisms of action of several compounds tested for CMT1A in pre‑clinical and clinical studies ascorbic acid, onapristone, PXT3003 (baclofen, naltrexone, and sorbitol), and ADX71441, very clearly indicates an important role for adenylyl cyclase activity and GPCRs in the pathomechanism of the disease. Metabotropic γ‑aminobutyric acid receptors (GABABR), subtype mu (μ) opioid receptors (MOR), and muscarinic acetylcholine receptors (mACh) appear to be particularly significant in both pathogenesis and treatment, and their activation may exert a similar and synergistic effect on the physiology of Schwann cells as well as neurons. These receptors participate in proliferation and differentiation of Schwann cells and influence excitatory transmission in neurons. We also hypothesize that onapristone might act through a non‑classical mechanism via membrane progesterone receptor (mPR) and cAMP signaling. This review endeavors to outline a pathway leading inversely from therapy to an indispensable role for adenylyl cyclase activity and GPCRs in the modulation of dosage sensitive peripheral myelin protein (PMP22) gene expression.

Charcot-Marie-Tooth type 1A drug therapies: role of adenylyl cyclase activity and G-protein coupled receptors in disease pathomechanism