Henry M. Colecraft
Columbia University, NY·Physiology
Every heartbeat and many brain signals depend on calcium ions flowing through channels in the cell membrane at the right time and place. When these calcium channels are misplaced, poorly controlled or mutated, the result can be heart failure or neurological disease.
- Fields
Physiology
Biophysics
Pharmacology
- Topics
calcium channels
CaV1.2
L-type calcium channel
- Grants
- 4 known grants, through Apr 2028
What they work on
- Elucidate how the inhibitory G-protein Rad is targeted to CaV1.2 calcium channels in heart cells, and how its release by protein kinase A raises calcium current during beta-adrenergic stimulation.
- Determine how the balance of kinases and phosphatases controls resting CaV1.2 activity in heart muscle cells, and engineer that balance by using nanobodies to bring kinases close to the channel.
- Develop tools to follow the movement, organization and regulation of CaV1.2 in live heart cells, using a mouse whose heart channels carry fluorescent and surface tags.
- Test whether engineered nanobodies that increase working CaV1.2 channels can prevent progression to heart failure after a heart attack in mice.
- Assess how loss-of-function mutations in the CaV1.2 subunit gene affect people, using genotype and health data from the Pakistan Genome Resource cohort.
- Define how CaV1.2 and the internal calcium-release channel RYR2 are regulated in normal and failing hearts, linking human mutations to structure-function studies from single molecules to mice.
- Measure how distinct CACNA1A mutations change CaV2.1 channel function at single-channel and whole-cell levels, and group them into classes that tailored corrective molecules could target.
- Model CACNA1A disorders in patient-derived iPSC neurons and mouse models, uncover how they cause disease, and test whether new bioengineered molecules correct the defects.
More about the research
The PI's projects study voltage-gated calcium channels, which open when a cell's electrical charge changes. They ask how these channels are organized and regulated inside cells, and how that goes wrong in disease. They also build new protein tools, especially engineered nanobodies (small antibody fragments), to switch channel activity up or down. In the heart, the focus is CaV1.2, the L-type calcium channel that is the main entry route for calcium into heart muscle cells and triggers each contraction. In the brain, the focus is CaV2.1 and its gene, CACNA1A.
Why it matters
Heart failure affects more than 6 million people in the United States, and heart disease is the leading cause of death worldwide. Clarifying how CaV1.2 and RYR2 calcium channels are controlled could reveal new drug targets. It could also yield nanobody-based agents that strengthen heart contraction or prevent heart failure after a heart attack. For patients with CACNA1A disorders such as hemiplegic migraine, ataxias and epileptic encephalopathies, sorting mutations into treatable classes could guide tailored corrective therapies.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Steven Marx
Columbia University, NY·Physiology
Determine how β-adrenergic stimulation of the CaV1.2 calcium channel changes in heart failure, using knock-in mice whose Rad brake protein cannot be phosphorylated by protein kinase A and mice lacking the Rad–beta-subunit interaction.
Manu Ben Johny
Columbia University, NY·Biophysics
Determine whether CaV2.1 and CaV2.2 calcium channels are S-palmitoylated, carrying an attached lipid group, in central and peripheral neurons, and how this modification alters channel activity.
Martin Morad
University of South Carolina-Columbia, SC·Physiology
Compare calcium-signaling defects caused by CPVT1 mutations in different regulatory regions of the cardiac calcium-release channel RyR2 in maturated human iPSC-derived heart cells, reverse them by editing the sequence back, and test drug responses.
The school
Columbia University: 89 labs on PI Pages, $1.4B a year on research, 625 research doctorates a year.
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