Studying the dynamic events that occur in the final stages of the secretory pathway (approach, docking, priming, and fusion) reveals a critical involvement of the myosin motor proteins in these later stages of both regulated and constitutive secretion (). Secretory vesicles or granules approaching the plasma membrane are transported by myosin Va, myosin 1e and myosin 1c along an F-actin filament path, probably as a multi-motor complex organized and regulated by myosin II. When the secretory vesicles/granules arrive at their precise location underneath the plasma membrane, they are tethered to the actin cytoskeleton and held in position by myosin 1c. They are then docked to the membrane by the direct interaction between myosin Va and the SNARE docking complex. Priming of these docked vesicles or granules for fusion relies on the membrane remodeling capabilities of myosin Va. Finally, fusion of primed secretory vesicles/granules is modulated by tension-based interactions of myosin VI, myosin II, and perhaps even myosin 1c with the F-actin cytoskeleton, which also regulate the dynamics (opening/closing) of the exocytic fusion pore.
The precise details of the involvement of each of these myosins in secretion at the molecular level however, still need to be elucidated. Which of the myosins act primarily as transporters, moving the secretory vesicles/granules to their correct locations in the cell, and which are mainly anchors, flexibly linking them to the dynamic actin (depolymerizing/repolymerizing) cytoskeleton? Could they work in both capacities depending on the identity of their adaptor/binding proteins? Which of their specific adaptor/binding proteins are involved in each precise step? Extensive further work will be required to identify and characterize the precise adaptor/binding protein for each of the myosins in different secretory cells. In addition, since it is likely that the myosins act cooperatively with over-lapping functions, it will be necessary to conduct future studies on the joint cellular functions of multiple motors, rather than examining each motor in isolation.
Further detailed studies on the roles of these myosins in secretion are particularly important due to the potential biomedical implications of their involvement in this process. It is possible that diseases linked to malfunctions in the final stages of secretion, such as Huntington’s disease [46
] and Alzheimer’s disease [47
], occur due to functional defects in the role of the myosins in these phases of the secretory pathways. Similarly, diseases arising from the improper function of myosins Ic/Ie/II/Va/VI, such as inclusion body myopathy [48
], Griscelli syndrome [49
], or hypertrophic cardiomyopathy [50
], could arise from an inability of these myosins to function properly in the secretory pathways. Future studies exploring the precise role of these myosins in secretion may therefore help us understand the pathogenesis of many modern diseases.