New approach to capture and characterize synaptic proteome

Liu, Xinan; Kadakkuzha, Beena M.; Pascal, Bruce D.; Steckler, Caitlin; Akhmedov, Komolitdin; Long, Yan; Chalmers, Michael J.; Puthanveettil, Sathyanarayanan V.

doi:10.1073/pnas.1401483111

Cited by 16 publications

(31 citation statements)

References 45 publications

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“…The human kinesin superfamily includes 45 genes, 38 of which are expressed in brain, with three subfamilies of kinesins that are predominantly responsible for cargo transport to the cell periphery (i.e., the synapse in neurons) (21,22,24,25,30,59,60). Kinesins are the major anterograde transporters of cargos that have been established as anesthetic targets, including mitochondria, GABA A receptors, syntaxin, and SNAP-25 (7,9,57,58,(61)(62)(63)(64).…”

Section: Discussionmentioning

confidence: 99%

Common general anesthetic propofol impairs kinesin processivity

Bensel

Guzik-Lendrum

Masucci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Propofol is the most widely used i.v. general anesthetic to induce and maintain anesthesia. It is now recognized that this small molecule influences ligand-gated channels, including the GABA A receptor and others. Specific propofol binding sites have been mapped using photoaffinity ligands and mutagenesis; however, their precise target interaction profiles fail to provide complete mechanistic underpinnings for the anesthetic state. These results suggest that propofol and other common anesthetics, such as etomidate and ketamine, may target additional protein networks of the CNS to contribute to the desired and undesired anesthesia end points. Some evidence for anesthetic interactions with the cytoskeleton exists, but the molecular motors have received no attention as anesthetic targets. We have recently discovered that propofol inhibits conventional kinesin-1 KIF5B and kinesin-2 KIF3AB and KIF3AC, causing a significant reduction in the distances that these processive kinesins can travel. These microtubule-based motors are highly expressed in the CNS and the major anterograde transporters of cargos, such as mitochondria, synaptic vesicle precursors, neurotransmitter receptors, cell signaling and adhesion molecules, and ciliary intraflagellar transport particles. The single-molecule results presented show that the kinesin processive stepping distance decreases 40-60% with EC 50 values <100 nM propofol without an effect on velocity. The lack of a velocity effect suggests that propofol is not binding at the ATP site or allosteric sites that modulate microtubule-activated ATP turnover. Rather, we propose that a transient propofol allosteric site forms when the motor head binds to the microtubule during stepping.anesthesia | allosteric inhibitor | microtubule | etomidate | ketamine

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Section: Discussionmentioning

confidence: 99%

Common general anesthetic propofol impairs kinesin processivity

Bensel

Guzik-Lendrum

Masucci

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…RNA deep sequencing studies show RyR2 transcripts in hippocampal neuropil and dendrites [2,19], and proteomic studies show RyR2 trafficking to synapses [89]. Interestingly, the transcription factor LMO4 (Lim only domain protein 4) is a positive regulator of RyR2 expression, and is one of the genes identified in a GWAS study of aging [157] whose protein expression patterns are altered in the entorhinal cortex and hippocampus, both vulnerable brain regions in AD [82].…”

Section: Early Transcriptomic and Proteomic Evidencementioning

confidence: 99%

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Briggs

Chakroborty

Stutzmann

2017

Biochemical and Biophysical Research Communications

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The current state of the AD research field is highly dynamic is some respects, while seemingly stagnant in others. Regarding the former, our current lack of understanding of initiating disease mechanisms, the absence of effective treatment options, and the looming escalation of AD patients is energizing new research directions including a much-needed re-focusing on early pathogenic mechanisms, validating novel targets, and investigating relevant biomarkers, among other exciting new efforts to curb disease progression and foremost, preserve memory function. With regard to the latter, the recent disappointing series of failed Phase III clinical trials targeting Aβ and APP processing, in concert with poor association between brain Aβ levels and cognitive function, have led many to call for a re-evaluation of the primacy of the amyloid cascade hypothesis. In this review, we integrate new insights into one of the earliest described signaling abnormalities in AD pathogenesis, namely intracellular Ca2+ signaling disruptions, and focus on its role in driving synaptic deficits – which is the feature that does correlate with AD-associated memory loss. Excess Ca2+release from intracellular stores such as the endoplasmic reticulum (ER) has been well-described in cellular and animal models of AD, as well as human patients, and here we expand upon recent developments in ER-localized release channels such as the IP3R and RyR, and the recent emphasis on RyR2. Consistent with ER Ca2+ mishandling in AD are recent findings implicating aspects of SOCE, such as STIM2 function, and TRPC3 and TRPC6 levels. Other Ca2+-regulated organelles important in signaling and protein handling are brought into the discussion, with new perspectives on lysosomal regulation. These early signaling abnormalities are discussed in the context of synaptic pathophysiology and disruptions in synaptic plasticity with a particular emphasis on short-term plasticity deficits. Overall, we aim to update and expand the list of early neuronal signaling abnormalities implicated in AD pathogenesis, identify specific channels and organelles involved, and link these to proximal synaptic impairments driving the memory loss in AD. This is all within the broader goal of identifying novel therapeutic targets to preserve cognitive function in AD.

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“…However it is not known whether Kif11, 21B and 13B regulate localization of a specific cargo. Previously we have reported that 29 Kif5C and Kif3A possess unique sets of protein cargos and are expressed in the same hippocampal neurons. Expressing multiple Kifs, each with specific effects on synaptic transmission and transport, will be advantageous to a neuron because these Kifs could be utilized for imparting specificity by differentially recruiting Kifs for regulating synapse function during development and plasticity.…”

Section: Discussionmentioning

confidence: 96%

“…Transported cargos include proteins such as Piccolo 12 , 26 , Neurexin 12 , 27 , Glutamate receptors 28 , 29 , organelles such as vesicles and mitochondria 30 , 31 and RNAs such as CaMK21 13 , 17 , 32 and BDNF 33 . Taken together these two broad functions suggest that Kifs might play a central role in regulating synapse function.…”

Section: Introductionmentioning

confidence: 99%

Kinesin Family of Proteins Kif11 and Kif21B Act as Inhibitory Constraints of Excitatory Synaptic Transmission Through Distinct Mechanisms

Swarnkar

Avchalumov

Raveendra

et al. 2018

Sci Rep

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Despite our understanding of the functions of the kinesin family of motor proteins (Kifs) in neurons, their specific roles in neuronal communication are less understood. To address this, by carrying out RNAi-mediated loss of function studies, we assessed the necessity of 18 Kifs in excitatory synaptic transmission in mouse primary hippocampal neurons prepared from both sexes. Our measurements of excitatory post-synaptic currents (EPSCs) have identified 7 Kifs that were found to be not critical and 11 Kifs that are essential for synaptic transmission by impacting either frequency or amplitude or both components of EPSCs. Intriguingly we found that knockdown of mitotic Kif4A and Kif11 and post-mitotic Kif21B resulted in an increase in EPSCs suggesting that they function as inhibitory constraints on synaptic transmission. Furthermore, Kifs (11, 21B, 13B) with distinct effects on synaptic transmission are expressed in the same hippocampal neuron. Mechanistically, unlike Kif21B, Kif11 requires the activity of pre-synaptic NMDARs. In addition, we find that Kif11 knockdown enhanced dendritic arborization, synapse number, expression of synaptic vesicle proteins synaptophysin and active zone protein Piccolo. Moreover, expression of Piccolo constrained Kif11 function in synaptic transmission. Together these results suggest that neurons are able to utilize specific Kifs as tools for calibrating synaptic function. These studies bring novel insights into the biology of Kifs and functioning of neural circuits.

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New approach to capture and characterize synaptic proteome

Cited by 16 publications

References 45 publications

Common general anesthetic propofol impairs kinesin processivity

Common general anesthetic propofol impairs kinesin processivity

Emerging pathways driving early synaptic pathology in Alzheimer's disease

Kinesin Family of Proteins Kif11 and Kif21B Act as Inhibitory Constraints of Excitatory Synaptic Transmission Through Distinct Mechanisms

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