Role of Clathrin and Dynamin in Clathrin Mediated Endocytosis/Synaptic Vesicle Recycling and Implications in Neurological Diseases

Abstract

Endocytosis is a process essential to the health and well-being of cell. It is required for the internalisation and sorting of “cargo”—the macromolecules, proteins, receptors and lipids of cell signalling. Clathrin mediated endocytosis (CME) is one of the key processes required for cellular well-being and signalling pathway activation. CME is key role to the recycling of synaptic vesicles [synaptic vesicle recycling (SVR)] in the brain, it is pivotal to signalling across synapses enabling intracellular communication in the sensory and nervous systems. In this review we provide an overview of the general process of CME with a particular focus on two key proteins: clathrin and dynamin that have a central role to play in ensuing successful completion of CME. We examine these two proteins as they are the two endocytotic proteins for which small molecule inhibitors, often of known mechanism of action, have been identified. Inhibition of CME offers the potential to develop therapeutic interventions into conditions involving defects in CME. This review will discuss the roles and the current scope of inhibitors of clathrin and dynamin, providing an insight into how further developments could affect neurological disease treatments.

Prodrugs of the Archetypal Dynamin Inhibitor Bis‐T‐22

“…Flash chromatography was carried out using silica gel 200-400 mesh (60 Å). 1 H and 13 C NMR were recorded at 300 MHz and 75 MHz respectively using a Bruker Avance 300 MHz spectrometer in CDCl 3 and DMSO-d 6 . GCMS was performed using a Shimadzu GCMS-QP2100.…”

“…Yield 4.95 g (81 %) mp 146 °C (Lit [148] °C). [29] 1 H NMR (DMSOd 6 ): 1.55 (quin, J = 6.9 Hz, 2H), 3.08 (q, J = 6.9 Hz, 4H), 3.60 (s, 4H), 8.22 (br s, 2H); 13 C NMR (DMSO-d 6 ): 25.3 (2C), 28.5, 36.9 (2C), 116.2 (2C), 162.1 (2C).…”

“…1 H NMR (DMSO-d 6 ): 1.77 (m, 2H), 2.32 (s, 12H), 3.28 (m, 4H, obscured), 7.49 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 1.9 Hz, 2H), 7.89 (dd, J = 1.9, 8.5 Hz, 2H), 8.17 (s, 2H), 8.48 (br t, J = 5.5 Hz, 2H). ; 13…”

Cellular and structural insight into dynamin function during endocytic vesicle formation: a tale of 50 years of investigation

“…A myristoylated, cell permeable version of D15 has been used [44,46] and is commercially available. Early blockers of endocytosis, such as chlorpromazine, monodansylcadaverine or potassium depletion, lack specificity (see [120] for a comprehensive review). In 2006, a small molecule screen on dynamin GTPase activity identified dynasore as a non-competitive, cell permeable inhibitor of CME with minimal acute cell toxicity [60].…”

“…Nevertheless, both dynasore and dyngo4a are not specific for dynamins: they also block the mitochondrial dynamin-related protein Drp1 [60] and block fluid-phase endocytosis and membrane ruffling in dynamin TKO cells [8]. Other dynamin inhibitors have been developed, targeting either the binding of PHD to membranes or directly the GTPase activity [120]. Among them, dynole 2-24 [127] shows the best combination of high potency (IC50 of 1.9 μM for inhibition of Tfn uptake), cell permeability and low cytotoxicity.…”