[7] While a graduate student in Prof. Solomon Snyder’s lab, Bredt discovered and characterized the family of enzymes that generate nitric oxide (NO).
Whereas a single measurement of endogenous NO had previously required complex and laborious methods, Bredt developed a simple, sensitive, and specific assay that monitored the conversion of [3H]arginine to [3H]citrulline.
In addition, he determined that NOS is a calmodulin-dependent enzyme (PNAS, 1990), which explained how NO is generated rapidly following glutamate-mediated increases in synaptic calcium.
In the peripheral nervous system, he found nNOS enriched in non-adrenergic, non-cholinergic neurons that innervate gastrointestinal and vascular smooth muscle (Nature, 1990).
These findings opened a gateway to investigating how NO participates in diverse physiology processes including aspects of peristalsis and penile erection (Science, 1992).
As excitotoxic neuronal death associated with cerebral ischemia involves excessive NO production downstream of NMDA receptors (PNAS, 1991), Bredt’s research pointed to exploitation of the antagonism of the NMDA receptor/PSD-95/nNOS complex as a stroke treatment (Journal of Biological Chemistry, 1999), which has shown promising clinical outcomes (Nature Reviews Drug Discovery, 2020).
They discovered a selective loss of nNOS from skeletal muscle sarcolemma in patients with Duchenne and Becker dystrophies, which involve dystrophin mutations (Journal of Experimental Medicine, 1996).
Bredt and Nicoll determined that a then recently discovered protein, stargazin, links PSD-95 to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subclass of glutamate receptors (Nature, 2000).
Bredt’s team at Janssen assessed whether analogous protein accessories might enable drug discovery for previously intractable and medically-important nicotinic acetylcholine receptors (nAChRs).
In a study, Bredt’s team used an innovative genome-wide cloning strategy to search systemically for neuronal proteins that could reconstitute the α7 nAChR subtype.
His team found that NACHO engages N‐glycosylation and endoplasmic reticulum chaperone pathways for Alpha-7 nicotinic receptor oligomerization and membrane trafficking (Cell Reports, 2020).
On November 17, 2021, the Wall Street Journal identified Dr. Bredt as co-author of an anonymous FDA citizen petition to halt phase 3 trials of simufilam, a drug from Cassava Sciences which targets protein misfolding for treatment of Alzheimer's disease.