Regulation of motor-cargo binding. A) Basic modes of motor-cargo interaction. Several distinct mechanisms are found that dock molecular motors onto cargos - interaction with phospholipids, receptors or integral membrane proteins, other motor proteins, scaffolding proteins, signaling proteins, such as kinases and phosphatases, and small Rab GTPases and their effector proteins. (B-D) Regardless of the cargo or the nature of the motor-cargo interaction, it is clear that a very close connection exists between the regulation of membrane trafficking and the docking of motor proteins to specific cargo. Three recent examples show that tight regulation of the motor-cargo interaction facilitates transport specificity and cargo binding/release at synaptic locations. (B) Ca2+ dependent cargo recruitment and release. Activity stimulated influx of Ca2+ allows unfolding of myosin-V and subsequent binding to the Rab11 effector FIP2 on recycling endosomes containing AMPA receptors. Another example of Ca2+ regulated transport is Miro/Milton dependent transport of mitochondria. Upon binding of Ca2+, Miro is able to interact with KIF5's motor domain, thereby preventing microtubule interaction and inhibiting mitochondria transport. (C) CaMKII regulated cargo release. CaMKII dependent phosphorylation of the KIF17 releases NMDA receptor-containing vesicles. In an alternative model active CaMKII is responsible for the degradation of liprin-α1 in turn causing the release of LAR-containing cargo. (D) Rab GTPase dependent transport. Rab27 associates with TrkB vesicles via its effector protein Slp1. The TrkB/Slp1/Rab27 complex binds via CRMP2 to KIF5 and allows transport of TrkB vesicles. Another study shows that Rab3 effector DENN/MADD is an adaptor between KIF1Bβ/KIF1A motors and Rab3-carrying vesicles. Neuronal activity might cause cargo release by activating Rab GTPase-activating proteins (GAPs). NMDAR, NMDA receptor; LAR, leukocyte antigen-related tyrosine phosphatase; AMPAR, AMPA receptor; Mito, mitochondrion; SV, synaptic vesicle; CaMKII, calcium calmodulin dependent kinase; FIP2, Rab11-family interactin protein 2; MyoVb, Myosin Vb; Slp1, synaptotagmin-like 1; TrkB, tyrosine receptor kinase B; CRMP-2, Collapsin response mediator protein 2; DNENN/MADD, differentially expressed in normal versus neoplastic/mitogen-activated protein kinase (MAPK) activating death domain.