The Hansen lab studies membrane mediated mechanisms of disease. Our current research has three areas of focus, the mechanism of general anesthesia/pain, Alzheimer’s disease (AD), and membrane mediated viral entry.

Anesthesia: For 150 years, anesthetics were thought to have a target in the plasma membrane (the oily part of a cell). But no mechanism could explain how the membrane could affect machinery that fires a nerve. Major finding: In 2020 the Arif Pavel in the Hansen lab showed that anesthetics could indirectly regulate an ion channel by disrupting cholesterol in the plasma membrane. The anesthetics bind to a hydrophobic surface generated by cholesterol and compete out protein that bind the same surface. This selective displacement of a protein activated an ion channel TREK-1.

Alzhiemer’s disease (AD): The number one genetic marker for late onset or sporadic AD is the presence apolipoprotein E (apoE) subtype 4. ApoE is a cholesterol carrier protein. In the brain cholesterol is made in astrocytes. Major Finding: Hao Wang in the Hansen lab showed that cholesterol made in the astrocyte is transported to the neuron where it acts as a signaling lipid to control the production of amyloid proteins. (Wang PNAS 2021)

Substrate presentation: We asked the question, where to proteins go when they leave cholesterol domains? Major finding: Nick Peterson in the lab discovered that proteins moves nanoscopic distances from cholesterol domains to PIP2 domains (Nature Communication 2016). The distances are nanoscopic (<200 nm). The discovery was made with super resolution imaging and opens up a whole new field of nanoscopic trafficking in the plasma membrane. Proteins that are trafficked in this way include the ACE2 receptor involved in SARS-CoV-2 infection and the amyloid proteins involved in AD.

We use a multidisciplinary approach to solve challenging longstanding questions. The lab is expert at super resolution imaging, electrophysiology, enzymology, membrane protein purification, and drug discovery.

Membrane mediated General Anesthesia

Cholesterol domains are ordered and selectivity bind the saturated lipid palmitate (a saturated 16 carbon lipid). Once covalently attached to a protein, palmitate targets a protein to cholesterol domains. The palmitate binds to a hydrophobic surface catalyzed by the cholesterol. Anesthetics also bind to the same hydrophobic surface and compete out the palmitate. The proteins lose their ability to bind to cholesterol domains causing them to leave the cholesterol domain. This selective displacement of a protein activated an ion channel TREK-1.

Molecular mechanism of membrane mediated anesthesia: A) Ordered cholesterol domains (blue colored lipids) are shown from the top of the membrane (Pavel PNAS 2020). Anesthetics (orange hexagon) insert into the membrane and compete out proteins with affinity for cholesterol. B) Ordered cholesterol domains shown from the side. Cholesterol creates a hydrophobic surface that a palmitate (16 carbon lipid) binds to. A protein is localized to cholesterol domains by covalently attaching a palmitate to the protein. When anesthetics insert into the membrane they compete for the palmitate binding site. Displacement of the protein

Alzheimer’s disease

Alzheimer’s disease is characterized by a loss of neuronal function and eventual death. The most common form is late onset or sporadic AD. The number one genetic marker for sporadic AD is the presence apolipoprotein E (apoE) subtype 4. ApoE is a cholesterol carrier protein. In the brain cholesterol is produced in astrocytes. Importantly AD patients have high brain cholesterol. Previous work connected astrocyte cholesterol with the synthesis of amyloid proteins in neurons. Current research is focused on the reversal of high cholesterol with ultrasound. Similar to anesthetics, the mechanical force disrupts the interaction of the palmate with cholesterol domains.

In the brain cholesterol is made in astrocytes. The cholesterol is transported to the neurons by apolipoprotein E (apoE). Once in the neuron cholesterol regulates the formation of amyloid proteins by substrate presentation. Wang PNAS 2021
Raft imaging graphic
Top a membrane mediated mechanism of mechanosensation. Top, mechanical force disrupts lipid interaction as opposed to storing the energy. Bottom Super resolution imaging of Cholesterol domains in live cells. (Petersen Nature Comm 2016)

Lipid gating of ion channels

We are developing the tools to measure lipids binding to ion channels and the cellular siganaling from lipid agonism. Ion channels harbor lipid binding sites for low abundant signaling lipids. The lipids diffuse in the membrane similar to neurtransmitter signals that diffuse in the synapse. When they bind the channel they cause a conformational change that opens the channel. We are studing the pharmacology and structural underpinnings of lipid gating of ion channels, i.e. “lipid-gated” ion channels.

Lipid gating of ion channels