Phospholipase Cβ (PLCβ)
cleaves phosphatidylinositol-4,5-bisphosphate (PIP<sub>2</sub>) into the second
messengers inositol-1,4,5-triphosphate (IP<sub>3</sub>) and diacylglycerol
(DAG). IP<sub>3</sub> increases intracellular Ca<sup>2+</sup>, while DAG
remains in the membrane, and together with increased Ca<sup>2+</sup>, activates
protein kinase C (PKC). PLCβ has low basal activity but is activated following stimulation
of G<sub>i</sub>- and G<sub>q</sub>-coupled receptors through direct
interactions with Gα<sub>q</sub> and Gβγ. PLCβ is essential for normal
cardiomyocyte and vascular smooth muscle function and regulates cell proliferation,
survival, migration, and differentiation. However, increased PLCβ activity and
expression results in arrhythmias, hypertrophy, and heart failure. PLCβ must
interact with the cell membrane for its activity. While heterotrimeric G
proteins stimulate PLCβ, they are insufficient for full activation, suggesting
the membrane itself contributes to increased lipid hydrolysis, potentially via
interfacial activation. However, how the composition of the membrane and its
resulting properties, such as surface charge, contribute to adsorption and
interfacial activation is not well-established. Furthermore, whether or how
interfacial activation also impacts other regulatory elements in PLCβ and Gα<sub>q</sub>-dependent
activation is unknown. Using an innovative combination of atomic force
microscopy on compressed lipid monolayers and biochemical assays, we are
beginning to understand how the membrane itself, PLCβ autoinhibitory elements
and Gα<sub>q</sub> regulate PLCβ activation. These studies provide the first
structure-based approach to understanding how the cell membrane regulates the
activity of this essential effector enzyme.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8636588 |
| Date | 13 August 2019 |
| Creators | Brianna N Hudson (6901280) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Insights_into_the_Role_of_the_Membrane_on_Phospholipase_C_Beta_and_G_Alpha_Q-Mediated_Activation/8636588 |
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