title: Proadrenomedullin N-terminal 20 peptide increases kinesin's velocity both in vitro and in vivo.
abstract: Intracellular cargo transport relies on microtubules and motor proteins such as kinesins and dyneins. Currently we have ample knowledge of the mechanisms by which motor proteins propel themselves along the microtubules, but little is known about intracellular factors that regulate motor speed. Here we show that proadrenomedullin N-terminal 20 peptide (PAMP) increases kinesin velocity and ATP consumption in a dose-dependent manner, using a variety of human kinesins. Structure-activity studies found that the terminal amide of PAMP is required for modulating kinesin activity and that the smallest peptide fragment retaining this role is PAMP₁₂₋₂₀. On the other hand, peptide fragments as small as PAMP₁₈₋₂₀ maintained the ability of delaying tubulin polymerization, another function previously described for PAMP, indicating that these two activities depend on different regions of the molecule. To demonstrate that these observations are also relevant in vivo, hippocampal neurons were isolated from mice lacking the gene coding for PAMP and from wild type littermates. Intravital stains followed by time-lapse microscopy analysis revealed that mitochondrial speed inside neurons lacking PAMP was significantly slower than in cells expressing the peptide. External addition of synthetic PAMP reversed this phenotype in PAMP-null neurons. Besides the obvious implications for better understanding cell biology, these results may be also relevant for the rapidly evolving discipline of nanotechnology because PAMP may be used as an accelerator of nanodevices based on microtubules and motor proteins.
authors.affiliation: Angiogenesis Study Group, Oncology Area, Center for Biomedical Research of La Rioja, 26006 Logroño, Spain.
authors.forename: Ignacio M
authors.initials: IM
authors.lastname: Larráyoz
authors.forename: Alfredo
authors.initials: A
authors.lastname: Martínez
mesh_terms: D000251:Adenosine Triphosphatases / Q000187:drug effects / Q000378:metabolism; D053607:Adrenomedullin / Q000172:deficiency / Q000494:pharmacology* / Q000502:physiology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D016547:Kinesins / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D058105:Polymerization
chemical_list: D053607:Adrenomedullin; D000251:Adenosine Triphosphatases; D016547:Kinesins