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Structural and Functional Investigation of Human Calcium Homeostasis Modulator 2 (CALHM2) Under Native Conditions

Award Number: F31NS149762
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Structural and Functional Investigation of Human Calcium Homeostasis Modulator 2 (CALHM2) Under Native Conditions - PROJECT SUMMARY Temperature sensitivity in ion channels has traditionally been studied in dedicated thermosensors such as the Transient Receptor Potential (TRP) family. However, all mammalian ion channels function at physiological body temperature, and growing evidence suggests that temperature broadly influences their biophysical and regulatory properties. This proposal focuses on the temperature-dependent gating of a non-canonical temperature sensitive channel, calcium homeostasis modulator 2 (CALHM2)—a large pore, voltage-gated, extracellular Ca2+-inhibited channel implicated in neurological disorders such as depression, Alzheimer’s disease, and ischemia. Although CALHM2 has been structurally characterized by our lab and others, its function as an ion channel remained controversial due to lack of robust conductance. We have recently discovered that CALHM2 is a bona fide ion channel only at physiological temperature. This finding reveals a critical and previously unrecognized role for temperature in regulating CALHM2 function. CALHM2 mediates ATP release and is abundantly expressed in the brain, contributing to neuronal excitability and purinergic signaling. Despite exciting structural characterization of CALHM2, its gating mechanism and regulatory principles remain unclear. The central objective of this proposal is to elucidate how extracellular Ca2+ and physiological temperature regulate CALHM2 gating and conformational dynamics, and how these signals are integrated at the molecular level. To achieve this, we will combine single-particle cryo-electron microscopy (cryo-EM) with patch-clamp electrophysiology. We will first characterize the temperature dependence of CALHM2 function by assessing its voltage gating properties under physiological temperature and in conditions with or without extracellular Ca2+. We will also examine the pharmacological effects of small-molecule inhibitors on channel activation and inhibition at various temperatures to probe pharmacological sensitivity and define the gating mechanism. For the structural component, we will use styrene maleic acid (SMA) copolymers and proteoliposomes to reconstitute CALHM2 in native-like lipid environments, capturing the channel in both its active and Ca2+-inhibited states. The resulting structures in tandem with the data from functional studies will allow for elucidation of the molecular mechanism underlying CALHM2 gating and function. Together, these integrated functional and structural data will provide a comprehensive view of CALHM2 gating and regulation under native conditions. The expected outcomes of this research will establish CALHM2 as a temperature-sensitive ion channel and reveal how Ca2+ and temperature modulate its activity. These insights will have broad implications for understanding ion channel physiology under native conditions and could enable the development of new therapeutic strategies for neurological disorders involving dysregulated ATP signaling.


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 = $44,703 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/11/2026	NEW	$0
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2026	NEW	$44,703
														Subtotal = $44,703

Grand Total All Awards = $44,703

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Structural and Functional Investigation of Human Calcium Homeostasis Modulator 2 (CALHM2) Under Native Conditions

Award Number: F31NS149762

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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