Biology subjects

Hammond, G. R.

Publications and source records attributed to Hammond, G. R..

21 records · Page 2Linked to original sources

bioRxiv2019

Probing the Subcellular Distribution of Phosphatidylinositol Reveals a Surprising Lack at the Plasma Membrane

The polyphosphoinositides (PPIn) are central regulatory lipids that direct membrane function in eukaryotic cells. Understanding how their synthesis is regulated is crucial to revealing these lipids role in health and disease. PPIn are derived from the major structural lipid, phosphatidylinositol (PI). However, although the distribution of most PPIn have been characterized, the subcellular localization of PI available for PPIn synthesis is not known. Here, we have used several orthogonal approaches to map the subcellular distribution of PI, including localizing exogenous fluorescent PI, as well as detecting lipid conversion products of endogenous PI after acute chemogenetic activation of PI-specific phospholipase and 4-kinase. We report that PI is broadly distributed throughout intracellular membrane compartments. However, there is a surprising lack of PI in the plasma membrane compared to the PPIn. These experiments implicate regulation of PI supply to the plasma membrane, as opposed to regulation of PPIn-kinases, as crucial to the control of PPIn synthesis and function at the PM. SummaryZewe et al develop approaches to map the subcellular distribution of the major phospholipid, phosphatidylinositol (PI), revealing that the lipid is present in most membranes except for plasma membrane, where it is mainly found as PI4P and PI(4,5)P2.

cell biology↗

bioRxiv2019

Characterising the balance between short-interval intracortical inhibition and short-interval intracortical facilitation in younger and older adults.

News and noteworthyO_LIMeasures of short-interval intracortical inhibition (SICI) and facilitation (SICF) reflect a balance between the excitability of inhibitory and facilitatory circuits in the motor cortex.\nC_LIO_LISICI stimulus-response functions, measured with a range of conditioning stimulus intensities and two intervals (first peak and trough of the SICF function), were similar between younger and older adults, except at the shift from net inhibition to facilitation.\nC_LIO_LIRelationships between SICI and SICF and manual dexterity show that an inhibition-facilitation balance favouring inhibition is associated with better manual dexterity and a balance favouring facilitation is associated with poorer manual dexterity.\nC_LI\n\nAbstractResearch investigating age-related differences in intracortical inhibition acting within the primary motor cortex (M1) reports inconsistent results. Age-related changes in the balance of inhibition and facilitation acting within M1 might underlie the inconsistent findings. Here, paired-pulse TMS was used to examine the balance between short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) in younger (n=26) and older (n=21) adults. First, the inter-stimulus intervals (ISIs) that produced maximal and minimal SICF at the first peak and trough were identified for each individual. Second, SICI stimulus-response functions (conditioning stimulus (CS): 50-110% resting motor threshold) were determined at ISIs that produced maximal and minimal facilitation for each individual. When SICI was measured with the ISI that produced maximal facilitation, the shift from net inhibition to net facilitation occurred at a lower CS intensity in older than younger adults. When SICI was measured with the ISI that produced minimal facilitation, older adults showed a persistent net inhibition at the highest CS intensity, whereas younger adults showed a shift from net inhibition to net facilitation at high CS intensities. Relationships between SICI and SICF and manual dexterity were evident across all measures of the inhibition-facilitation balance, whereby a balance favouring inhibition is associated with better manual dexterity and a balance favouring facilitation is associated with poorer manual dexterity. These findings contribute to our understanding of age-related differences in intracortical inhibitory and facilitatory processes, as well as highlight the importance of considering the balance between inhibitory and facilitatory processes when measuring SICI and SICF.

neuroscience↗

bioRxiv2018

A High Avidity Biosensor Reveals PI(3,4)P2 is Predominantly a Class I PI3K Signaling Product

Class I PI 3-kinase (PI3K) signaling is central to animal growth and metabolism, and disruption of this pathway occurs frequently in cancer and diabetes. However, the specific spatial/temporal dynamics and signaling roles of its minor lipid messenger, phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2], are not well understood. This owes principally to a lack of tools to study this scarce lipid. Here, we developed a high sensitivity genetically encoded biosensor for PI(3,4)P2, demonstrating high selectivity and specificity of the sensor for the lipid. We show that despite clear evidence for class II PI3K in PI(3,4)P2-driven function, the overwhelming majority of the lipid accumulates through degradation of class I PI3K-produced PIP3. However, we show that PI(3,4)P2 is also subject to hydrolysis by the tumor suppressor lipid phosphatase PTEN. Collectively, our results show that PI(3,4)P2 is potentially an important driver of class I PI3K-driven signaling, and provides powerful new tools to begin to resolve the biological functions of this lipid downstream of class I and II PI3K.

cell biology↗