TRPML Channels in Function, Disease, and Prospective Therapies

The transient receptor potential mucolipin (TRPML) subfamily of transient receptor potential cation channels consists of three members (TRPML1-3) that function at various stages of endocytosis. Conventional research in the TRPML field suggests that dysfunction along these endocytic stages underlies the severe psychomotor impairment in mucolipidosis type IV (MLIV). However, recent studies �intimate that TRPMLs may be implicated in other neuropathological disorders as well. This review follows the historical development of TRPML research from the clinical description of the first MLIV patient until present-day characterization of TRPML1-based defects in MLIV on the molecular and cell biological �levels. In addition, the aberrant role of TRPML3 in varitint-waddler mouse pathology is elucidated and the normal function of the protein and its paralogs are described. TRPML electrophysiology, pharmacology, and animal models are discussed and TRPML-associated systemic and neurological disorders, not including MLIV, are also addressed. Recently, a number of prospective TRPML-based therapies have been proposed in the treatment of these disorders. These prospects are carefully considered here as well. Altogether, the aforementioned descriptions aim to highlight the transformation of TRPML research from a single discipline, single gene, and single disorder field into a multidisciplinary, multigene endeavor with wide application to therapeutic treatment of several neurobiological disorders.