Negative regulatory mechanism of mechanically activated PIEZO2 channels by TMEM120A/tacan
Ended Project Grant Awarded Last action
- Award ID
- F31NS135951
- Recipient
-
Rutgers The State University Of New Jersey UEI YVVTQD8CJC79
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $130,039
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date
- Place of performance
- New Jersey, USA
Award details come from USAspending.gov.
Description
- Abstract
- Mechanically activated PIEZO2 channels are highly expressed in dorsal root ganglion (DRG) neurons mediating light touch sensing and proprioception. While PIEZO2 is crucial for these sensory functions, little is known about auxiliary proteins regulating its mechanosensitivity. We have identified TMEM120A (tacan) as a robust and specific negative regulator of PIEZO2 channels. TMEM120A was initially proposed to be a novel ION channel in DRG neurons contributing to mechanosensitivity. We were unable to reproduce mechanically activated currents from TMEM120A along with several other groups. TMEM120A's structure does not resemble any known ION channel, but IT does have structural homology to elongation of very long chain fatty acids 7 (ELOVL7). Directly supplementing cells with dietary fatty acids or activating lipid modifying enzymes can inhibit or prolong the activation of mechanically activated ION channels. In cells CO-expressing PIEZO2 and TMEM120A, we observed a significant reduction in PIEZO2 mediated peak current amplitudes, but we did not observe any changes to PIEZO1 or trek-1 in TMEM120A's presence. Using liquid chromatography tandem mass spectrometry (LC- MS/MS), we have identified a robust upregulation of lipids in TMEM120A expressing cells such as lysophosphatidic acid, and phosphatidic acid. We also began determining whether TMEM120A's lipid modifying function is necessary for PIEZO2 inhibition. A single point mutation to a hypothesized catalytic residue within TMEM120A resulted in significantly less PIEZO2 inhibition compared to wildtype. Supplementing cells with dioctanoyl-phosphatidic acid (a lipid upregulated by TMEM120A) robustly inhibited PIEZO2 channel activity but did not affect PIEZO1 activity. Using a light activated phospholipase d (opto-PLD) that generates phosphatidic acid from existing lipids in the membrane (predominantly from phosphatidylcholine), we observed significant PIEZO2 inhibition but not PIEZO1. Our preliminary data indicate that TMEM120A specifically inhibits PIEZO2 channels by upregulating phosphatidic acid. Finally, we show preliminary data indicating that extracellular application of carbacyclic phosphatidic acid (a cyclic analog of phosphatidic acid) reduces PIEZO2 current amplitudes. Carbacyclic phosphatidic acid's head group forms a ring structure with the glycerol backbone reducing the likelihood of IT being metabolized into lysophosphatidic acid or phosphatidic acid. Additionally, administration of carbacylcic phosphatidic acid has been reported to alleviate mechanical pain in animal models. The mechanism for this analgesic function remains an intriguing and open question. We propose further investigation necessary to better assess how TMEM120A's putative lipid modifying function specifically inhibits PIEZO2 channels. We also propose further inquiry to determine whether carbacyclic phosphatidic acid administration is sufficient to inhibit PIEZO2 channels in DRG neurons and reduce PIEZO2 mediated mechanosensation (light touch and inflammatory mechanical allodynia). Generating additional knowledge of this robust regulatory event will have a substantial impact in our understanding of mechanosensation.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$545 | |
| Amendment | -$1,080 | |
| Amendment | $1,280 | |
| Amendment | $1,280 | |
| Amendment | $32,276 | |
| Amendment | $32,276 | |
| Amendment | $0 | |
| Amendment | $32,276 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Original award | $32,276 |
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Quick answers
Who received award F31NS135951?
F31NS135951 was awarded to Rutgers The State University Of New Jersey by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on July 26, 2024.
How much is award F31NS135951 worth?
$130,039 has been obligated on F31NS135951.
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