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Targeted Depalmitoylation of Presynaptic CaV channels in Health and Disease

Award Number: R01NS140214
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/02/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2031

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Targeted Depalmitoylation of Presynaptic CaV channels in Health and Disease - PROJECT SUMMARY CaV2.1/2.2 channels are physiologically consequential as they convey Ca2+ influx that initiates vesicular release of neurotransmitters at chemical synapses of both central and peripheral neurons. Not surprisingly, dysfunction of these channels is linked to various human diseases. First, loss-of-function missense mutations in CACNA1A gene that encodes the CaV2.1 channel are linked to severe neurological diseases including ataxia, epilepsy, and neurodevelopmental delay. Second, as CaV2.2 channels serve as key mediators of nociceptive signaling, pharmacological inhibition of CaV2.2 has emerged as a promising non-opioid approach for the treatment of chronic pain, although current FDA approved blockers (gabapentin, pregabalin, and ziconotide) have severe side-effects. New strategies to precisely tune the function of these channels in neurons are therefore highly desired. In this regard, in depth physiological studies have revealed that the localization and activity of CaV2 channels is tightly regulated by a bevy of molecular and cellular factors including alternative-splicing, phosphorylation, and the binding of auxiliary subunits and regulatory proteins. Here, our preliminary data uncovers S-palmitoylation of the pore-forming subunits of both CaV2.1 and CaV2.2 channels as a powerful and largely unexplored modulatory scheme. Unlike other lipid modifications, S-palmitoylation is reversible and dynamic, orchestrated by zDHHC1-23 enzymes that attach lipid groups to proteins and thioesterases that excise lipid modifications. We find that depalmitoylation of CaV2.2 channels potently inhibits Ca2+ currents, while the same maneuver upregulates CaV2.1. The overall goal of this proposal is to: (1) elucidate the physiological relevance of S-palmitoylation of CaV2 channels in both peripheral and central neurons and (2) to devise engineered depalmitoylases to selectively tune CaV2.1/2.2 function in pathophysiological settings. Our central hypothesis is that CaV2 channels are endogenously palmitoylated in neurons and targeted recruitment of a depalmitoylase to the channel complex can reverse pathophysiological changes in channel function. While this proposal focuses on CaV2 channels, the ultimate impact of the methods developed here extends to nearly a wide range of proteins that are S-palmitoylated, and potentially forms the basis for developing new therapeutics.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $589,156 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/2/2026	NEW	$589,156
														Subtotal = $589,156

Grand Total All Awards = $589,156

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Targeted Depalmitoylation of Presynaptic CaV channels in Health and Disease

Award Number: R01NS140214

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/02/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2031

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