Homeostatic control of inositol lipid signaling in asthma and vascular hypertension
Vascular hypertension and asthma are very different diseases, yet both share a common etiology: in each, over-contraction of the vascular or airway smooth muscle cells is central to pathogenesis. In airway and vascular smooth muscle, the PI(4,5)P2-coupled phospholipase C signaling pathway is central to transduce tonic or inflammatory stimuli into smooth muscle contraction. Many existing bronchodilating or vaso-relaxing therapies antagonize the various inputs into this central pathway, and these are often used in combination to attain greater therapeutic efficacy. However, to date there is little known about how modulating the convergent lipid signaling pathway itself might be used for therapeutic benefit. Our lab is investigating this topic at a fundamental cell biological level.
PI(4,5)P2 is a lipid specifically enriched in the cytoplasmic leaflet of cell membranes that regulates scores of proteins, thus controlling cell structure, nutrient important and export, as well as signal transduction. The phospholipase C pathway triggers PI(4,5)P2 breakdown to produce second messenger molecules that stimulate Ca2+-activated contraction. However, to sustain this signaling, and also to sustain the many other essential cellular functions associated with PI(4,5)P2, the cell must automatically adjust re-synthesis of the lipid to maintain a constant supply. This is a logistically demanding cellular exercise, employing up-regulation of several enzymes necessary for synthesis, as well as specialized transport machinery that rapidly re-cycles lipid breakdown products back to the ER for their re-assembly and their return to the plasma membrane. Despite the established importance of this complex cellular machinery, we still know almost nothing about how it is regulated. Our lab employs high-resolution imaging approaches to study the molecular dynamics employed by these signaling events in real-time at the single cell level. We are determining the key regulatory steps involved in PI(4,5)P2 re-synthesis, and how this modulates Ca2+-signaling output. We hope that this knowledge will lead to new therapeutic strategies to reduce pathological smooth muscle cell contraction in vascular hypertension and asthma.
(1) contractile hormones and inflammatory mediators activate G-protein coupled receptors at the cell surface, activating PLC inside cells to in turn (2) trigger calcium-release from internal SR stores to stimulate constriction of airways or blood vessels. (3) Calcium is continually removed from the cell by pumps and exchangers at the cell surface, so (4) calcium influx is required to sustain constriction. Note, all these steps require the lipid PI(4,5)P2. The action of medicines that relieve constriction is asthma and hypertension are indicated. The include ACE inhibitors, Angiotensin Receptor Blockers (ARB), Calcium Channel Blockers (CRB), anti-cholinergics and Inhaled Corticosteroids (ICS).