This project focuses on cardiac signaling pathways in which lipid metabolism, coupled to mitochondrial activity state, promote massive sarcolemma internalization via endocytosis (MEND) and/or massive ectosome shedding (MESS) to the extracellular space. The endocytosis pathway depends on fatty acid metabolism and the generation of cytoplasmic acyl-coenzyme A that is used to lipidate numerous sarcolemmmal proteins. The shedding pathway depends primarily on the generation of lysophosphatidylcholine, the activation of its receptors in the cardiac myocyte, and subsequent scrambling of sarcolemmal phospholipids between monolayers. Both mechanisms appear to depend on the generation of ordered membrane domains within the sarcolemma which then facilitate unique protein-protein interactions and functions. Both mechanisms are expected to play major roles in membrane remodeling that occurs in ischemia/reperfusion injury, as well as in major chronic, degenerative diseases involving oxidative stress. Using multiple mice lines with deficiencies in these pathways, as well as drugs to manipulate individual reactions, we will analyze the commonalities and distinctive traits of these pathways, identify the essential molecular players, factors that decisively push the sarcolemma to MEND or MESS, and define more precisely the physiological and pathological roles of MEND and MESS. The project will provide insight into fundamental cell regulatory mechanisms that have a high impact for an understanding of the leading causes of death in the developed world.
We recently discovered a cardiac signaling pathway in which mitochondrial metabolism controls the acylation of membrane proteins and thereby can initiate the massive internalization of cardiac surface membrane. We now extend this work to a variant process by which massive amounts of cardiac membrane are shed outwardly to the extracellular space of the heart. We are studying how these pathways are related and regulated, how they are used by the heart, and how they affect cardiac function in normal physiology as well as in life-or-death circumstances.
|Hilgemann, Donald W; Dai, Gucan; Collins, Anthony et al. (2018) Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis. J Gen Physiol 150:211-224|
|Schmiege, Philip; Fine, Michael; Li, Xiaochun (2018) The regulatory mechanism of mammalian TRPMLs revealed by cryo-EM. FEBS J 285:2579-2585|
|Lu, Fang-Min; Hilgemann, Donald W (2017) Na/K pump inactivation, subsarcolemmal Na measurements, and cytoplasmic ion turnover kinetics contradict restricted Na spaces in murine cardiac myocytes. J Gen Physiol 149:727-749|
|Dalton, George; An, Sung-Wan; Al-Juboori, Saif I et al. (2017) Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling. Proc Natl Acad Sci U S A 114:752-757|
|Schmiege, Philip; Fine, Michael; Blobel, Günter et al. (2017) Human TRPML1 channel structures in open and closed conformations. Nature 550:366-370|
|Lu, Fang-Min; Deisl, Christine; Hilgemann, Donald W (2016) Profound regulation of Na/K pump activity by transient elevations of cytoplasmic calcium in murine cardiac myocytes. Elife 5:|
|Reilly, Louise; Howie, Jacqueline; Wypijewski, Krzysztof et al. (2015) Palmitoylation of the Na/Ca exchanger cytoplasmic loop controls its inactivation and internalization during stress signaling. FASEB J 29:4532-43|
|Hilgemann, Donald W (2014) Cardiac electrophysiology delivered a ""grand slam"" by angiotensin II: the third explanation of transmural cardiac electrical activity gradients. Biophys J 106:2288-90|