Dnm1Edit
Dnm1, better known as dynamin-1, is a neuron-focused member of the dynamin family of large GTPases that drives the final pinching-off step in clathrin-mediated endocytosis. The gene DNM1 encodes this protein, which is highly enriched in nerve terminals and is central to the rapid recycling of synaptic vesicles after exocytosis. In the broader context of the cell, other dynamin family members such as DNM2 and DNM3 carry out similar fission tasks in different tissues, but dynamin-1 plays the dominant role in fast, activity-dependent endocytosis at chemical synapses. By hydrolyzing GTP, dynamin-1 powers conformational changes that drive membrane scission and vesicle reformation, enabling sustained neuronal communication.
Overview
Dynamin-1 operates at the interface between the plasma membrane and the cytoplasm, assembling into collars around the necks of budding vesicles. This assembly is regulated by multiple domains within the protein and by interactions with accessory endocytic proteins. The process is energy-dependent: GTP hydrolysis provides the mechanical force needed to constrict the membrane neck and release a vesicle back into the cytosol for reuse in neurotransmission. The efficiency and speed of this cycle are essential for high-frequency synaptic activity and for maintaining proper signaling in circuits that rely on rapid information processing.
Molecular architecture and mechanism
Dynamin-1 is a multi-domain GTPase with a modular design that supports its assembly and function. The catalytic GTPase domain sits at the N-terminus, followed by a middle domain that promotes oligomerization, a pleckstrin homology (PH) domain that helps recruit the protein to membrane surfaces, and a proline-rich domain (PRD) that mediates interactions with cytosolic adaptors and scaffolding proteins. In neurons, dynamin-1 collaborates with accessory proteins such as amphiphysin and endophilin to be targeted to sites of endocytosis, while other partners like dynamin-2 can provide redundancy under certain conditions. The current model posits that dynamin-1 forms helical structures around the necks of budding vesicles; GTP hydrolysis triggers a conformational change that tightens the spiral and effects membrane fission, releasing a vesicle for recycling.
In the neuronal context, this mechanism supports rapid reuse of synaptic vesicles after transmitter release. The balance between endocytosis and exocytosis is finely tuned, with kinases such as CaMKII and PKA capable of modulating dynamin-1 activity through phosphorylation and interactions with other regulatory proteins. The precise timing of these events is crucial for maintaining fidelity of signaling in neural networks and for preventing dysregulated neurotransmission.
Biological roles
Beyond its canonical role in endocytosis, dynamin-1 participates in broader aspects of synaptic physiology. By regulating the vesicle cycle, it supports sustained release during repetitive stimulation and helps shape short-term plasticity at many synapses. While dynamin-1 is the best-characterized neuronal dynamin, other dynamin family members contribute to endocytic and fission processes in different cellular contexts, including mitochondria-related fission mediated by DNM1L (often referred to as Drp1) in non-neuronal tissues. The specialization of dynamin-1 for neurons reflects evolutionary pressure to maintain high-speed vesicle turnover in circuits that underpin rapid processing and complex behaviors.
Genetic and molecular studies highlight that alterations in DNM1 can influence synaptic function. The gene is expressed most prominently in the brain, with activity-dependent regulation that aligns with periods of heightened synaptic demand. Its interactions with accessory proteins help coordinate cargo selection, timing, and membrane remodeling during vesicle recycling, making Dnm1 a cornerstone of synaptic efficiency.
Clinical significance
Variants in DNM1 have been linked to neurodevelopmental disorders and epileptic encephalopathies. A range of de novo and inherited mutations disrupt GTP hydrolysis, oligomerization, or interactions with partner proteins, leading to impaired synaptic vesicle recycling and aberrant neuronal excitability. Clinically, affected individuals may present with developmental delay, hypotonia, motor abnormalities, and seizures beginning in infancy or early childhood. The spectrum can include severe epileptic syndromes that persist despite standard therapies, reflecting the essential role of dynamin-1 in managing neurotransmission during early neural development.
Research on DNM1-related conditions informs our understanding of how precise endocytic control translates into neural circuit function. In some cases, mutations may exert dominant-negative effects or alter regulatory phosphorylation, complicating therapeutic approaches. Ongoing work aims to translate these molecular insights into targeted strategies that address the synaptic deficits at the heart of the disease.
Research and debates
Scientific discussions around dynamin-1 continue to refine the picture of its exact contributions to endocytosis and synaptic physiology. Key questions include the relative importance of dynamin-1 versus other dynamin isoforms in various neuron types and brain regions, and how dynamin-1 collaborates with BAR-domain proteins and actin dynamics during vesicle scission. Some lines of evidence support a model in which fast, clathrin-mediated endocytosis is driven primarily by dynamin-1 at active synapses, while other observations point to alternative endocytic pathways that can compensate when dynamin-1 function is disrupted. The use of pharmacological inhibitors (for example, dynasore-like compounds) and genetic models continues to illuminate which steps of the endocytic cycle depend on dynamin-1 and how these steps are coordinated with exocytosis.
In the context of disease, the investigation of DNM1 variants has prompted debate over how different mutations translate into cellular phenotypes. While some mutations appear to reduce GTPase activity or impair oligomerization, others may alter protein interactions or subcellular localization. Deciphering these mechanisms is critical for identifying potential therapeutic targets that can restore balanced endocytosis and neuronal signaling.