Distinct Roles of Myosin Va in Membrane Remodeling and Exocytosis of Secretory Granules

Kögel, Tanja; Rudolf, Rüdiger; Hodneland, Erlend; Hellwig, Andrea; Kuznetsov, Sergei A.; Seiler, Florian; Söllner, Thomas H.; Barroso, João Filipe; Gerdes, Hans‐Hermann

doi:10.1111/j.1600-0854.2010.01048.x

Cited by 22 publications

(36 citation statements)

References 56 publications

(75 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The pHluorin is a modified form of green fluorescent protein (GFP) with increased sensitivity to protons that is quenched at the low internal pH of LDCVs and therefore increases in fluorescence with exposure to the higher external pH on exocytosis. Since neuropeptide Y (NPY)-pHluorin has been shown to undergo regulated exocytosis [26], we used lentiviral transduction to express this fusion protein and monitored individual exocytotic events at the plasma membrane of living chromaffin cells. In the absence of stimulation, control cells showed very few spontaneous fusion events over 90 s of imaging, but AP-3-deficient mocha cells exhibited substantially more (Figure 1A–1B).…”

Section: Resultsmentioning

confidence: 99%

Widespread Dysregulation of Peptide Hormone Release in Mice Lacking Adaptor Protein AP-3

2013

View full text Add to dashboard Cite

The regulated secretion of peptide hormones, neural peptides and many growth factors depends on their sorting into large dense core vesicles (LDCVs) capable of regulated exocytosis. LDCVs form at the trans-Golgi network, but the mechanisms that sort proteins to this regulated secretory pathway and the cytosolic machinery that produces LDCVs remain poorly understood. Recently, we used an RNAi screen to identify a role for heterotetrameric adaptor protein AP-3 in regulated secretion and in particular, LDCV formation. Indeed, mocha mice lacking AP-3 have a severe neurological and behavioral phenotype, but this has been attributed to a role for AP-3 in the endolysosomal rather than biosynthetic pathway. We therefore used mocha mice to determine whether loss of AP-3 also dysregulates peptide release in vivo. We find that adrenal chromaffin cells from mocha animals show increased constitutive exocytosis of both soluble cargo and LDCV membrane proteins, reducing the response to stimulation. We also observe increased basal release of both insulin and glucagon from pancreatic islet cells of mocha mice, suggesting a global disturbance in the release of peptide hormones. AP-3 exists as both ubiquitous and neuronal isoforms, but the analysis of mice lacking each of these isoforms individually and together shows that loss of both is required to reproduce the effect of the mocha mutation on the regulated pathway. In addition, we show that loss of the related adaptor protein AP-1 has a similar effect on regulated secretion but exacerbates the effect of AP-3 RNAi, suggesting distinct roles for the two adaptors in the regulated secretory pathway.

show abstract

Section: Resultsmentioning

confidence: 99%

Widespread Dysregulation of Peptide Hormone Release in Mice Lacking Adaptor Protein AP-3

2013

View full text Add to dashboard Cite

show abstract

“…All these processes are tightly regulated and coordinated by the concerted action of a host of evolutionary conserved proteins. For example: syntaxin 6 and synaptotagmin IV are necessary for the homotypic fusion (Wendler et al 2001;Ahras et al 2006), while AP-1, ARF1, VAMP4, GGA, UNC-108/RAB-2, and myosin Va (Kakhlon et al 2006;Kogel et al 2010) have been found to participate in later stages of maturation (Edwards et al 2009;Sumakovic et al 2009). However, many of these components of the secretory apparatus regulate post Golgi-membrane trafficking more generally and are not unique to the DCV pathway.…”

mentioning

confidence: 99%

HID-1, a New Component of the Peptidergic Signaling Pathway

et al. 2011

View full text Add to dashboard Cite

hid-1 was originally identified as a Caenorhabditis elegans gene encoding a novel conserved protein that regulates the decision to enter into the enduring dauer larval stage. We isolated a novel allele of hid-1 in a forward genetic screen for mutants mislocalizing RBF-1 rabphilin, a RAB-27 effector. Here we demonstrate that HID-1 functions in the nervous system to regulate neuromuscular signaling and in the intestine to regulate the defecation motor program. We further show that a conserved N-terminal myristoylated motif of both invertebrate and vertebrate HID-1 is essential for its association with intracellular membranes in nematodes and PC12 cells. C. elegans neuronal HID-1 resides on intracellular membranes in neuronal cell somas; however, the kinesin UNC-104 also transports HID-1 to synaptic regions. HID-1 accumulates in the axons of unc-13 and unc-31 mutants, suggesting it is associated with neurosecretory vesicles. Consistent with this, genetic studies place HID-1 in a peptidergic signaling pathway. Finally, a hid-1 null mutation reduces the levels of endogenous neuropeptides and alters the secretion of fluorescent-tagged cargos derived from neuronal and intestinal dense core vesicles (DCVs). Taken together, our findings indicate that HID-1 is a novel component of a DCV-based neurosecretory pathway and that it regulates one or more aspects of the biogenesis, maturation, or trafficking of DCVs.

show abstract

“…It is present on SGs (Lejen et al, 2002;Varadi et al, 2005) and is involved in SG movement to the cell surface (Prekeris and Terrian, 1997; Rudolf et al, 2003;Eichler et al, 2006;Desnos et al, 2007;Kögel et al, 2010). Therefore, myosin Va and VI may have synergistic roles, with myosin VI acting in the recruitment and retention of SGs to the cortical actin network and myosin Va involved in the active transport of SGs toward the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Myosin VI small insert isoform maintains exocytosis by tethering secretory granules to the cortical actin

Tomatis¹,

Papadopulos²,

Malintan³

et al. 2013

J Gen Physiol

View full text Add to dashboard Cite

Distinct Roles of Myosin Va in Membrane Remodeling and Exocytosis of Secretory Granules

Cited by 22 publications

References 56 publications

Widespread Dysregulation of Peptide Hormone Release in Mice Lacking Adaptor Protein AP-3

Widespread Dysregulation of Peptide Hormone Release in Mice Lacking Adaptor Protein AP-3

HID-1, a New Component of the Peptidergic Signaling Pathway

Myosin VI small insert isoform maintains exocytosis by tethering secretory granules to the cortical actin

Contact Info

Product

Resources

About