About

Professor Lonny Levin is a researcher at Weill Cornell Medicine, leading the LevBuck Laboratory which focuses on the second messenger molecule cAMP. His work involves studying how cAMP modulates cell growth and differentiation across a range of organisms from bacteria to higher eukaryotes. Levin's laboratory has purified and cloned soluble adenylyl cyclase (sAC), a key enzyme involved in intracellular cAMP signaling, which is regulated by bicarbonate ions and functions as a sensor for carbon dioxide, bicarbonate, and pH. His research emphasizes the compartmentalization of cAMP within cells, exploring how distinct signaling microdomains are regulated and how sAC contributes to these processes. Levin's work advances understanding of intracellular signaling mechanisms and the role of second messengers in cellular function.

Research topics

• Internal medicine
• Cell biology
• Biology
• Medicine
• Genetics
• Biochemistry
• Andrology
• Endocrinology
• Environmental health
• Physiology
• Pharmacology
• Gynecology
• Chemistry
• Cancer research

Selected publications

• BPS2026 – Physico-chemical predictors of bilayer-modifying potency (cytotoxicity) in a library of sAC inhibitors

  Biophysical Journal · 2026-02-01

  article
  PublisherDOI

• Targeting soluble adenylyl cyclase for on-demand contraception

  Physiology · 2026-03-17

  articleOpen accessSenior author

  Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily ancient, intracellular source of cAMP that is molecularly and mechanistically distinct from the more widely studied, hormone-responsive, G protein regulated transmembrane adenylyl cyclases. Unlike other mammalian cyclases, sAC is most abundantly expressed in male germ cells and is directly regulated by bicarbonate and calcium. Genetic and pharmacological evidence in rodents and humans establishes sAC as essential for male fertility: loss of sAC activity yields immotile sperm incapable of fertilizing the egg resulting in male-specific infertility. These features position sAC as a promising target for developing nonhormonal, on-demand contraceptives suitable for men and women. A proof-of-concept inhibitor has demonstrated a rapid, reversible contraceptive effect in vivo in mice, but translation to a clinical product must address challenges inherent to on-demand sperm-targeted pharmacology. In addition to ensuring a high safety margin and navigating an emerging regulatory and commercial landscape, common to any male contraceptive, on-demand male contraception must define onset/duration of efficacy while ensuring persistent inactivation of sperm function after ejaculation.

  PublisherDOI

• Bovine serum albumin‐induced calcium influx triggers soluble adenylyl cyclase activation and cyclic AMP signalling pathways in mouse sperm capacitation

  The Journal of Physiology · 2025-05-01 · 5 citations

  articleOpen access

  Abstract Sperm capacitation involves a series of biochemical and physiological changes essential for fertilization. A critical regulator of capacitation, the soluble adenylyl cyclase (sAC; ADCY10 )‐dependent production of the second messenger cyclic AMP (cAMP), drives key downstream events such as protein kinase A (PKA) substrate phosphorylation. sAC activity is directly stimulated by bicarbonate (HCO 3 − ) and calcium (Ca 2+ ). CatSper, a sperm‐specific Ca 2+ channel, is considered the primary pathway for Ca 2+ influx during capacitation; however, emerging evidence suggests additional pathways exist. This study reveals that bovine serum albumin (BSA) influences the dynamics of intracellular Ca 2+ concentration ([Ca 2+ ] i ) in CatSper1 knockout (KO) sperm and plays a novel role in sAC activation. Using single‐cell live imaging and flow cytometry, we observed a rapid [Ca 2+ ] i rise in the head of CatSper1 KO sperm under capacitating conditions, indicating an alternative Ca 2+ entry mechanism. BSA alone, in the absence of HCO 3 − , triggered a significant [Ca 2+ ] i rise. Removal of extracellular Ca 2+ abolished this [Ca 2+ ] i rise, confirming the necessity of Ca 2+ influx. This BSA‐induced [Ca 2+ ] i rise was upstream of sAC activation, since it was not affected by sAC inhibitors and led to increased cAMP production and PKA substrate phosphorylation. Our findings provide new insights into the regulatory mechanisms of sAC, highlighting the existence of a CatSper‐independent Ca 2+ entry pathway activated by BSA during sperm capacitation. This rapid [Ca 2+ ] i rise is initiated in the sperm head and propagates throughout the cell, and is sufficient to activate sAC and stimulate cAMP synthesis independently of HCO 3 − . image Key points Sperm capacitation, essential for fertilization, is regulated by sAC, which produces cAMP in response to HCO 3 − and Ca 2+ , driving key events like protein kinase A substrate phosphorylation. We demonstrate the existence of a CatSper‐independent Ca 2+ entry pathway that initiates in the sperm head and propagates throughout the cell, occurring rapidly after sperm encounters albumin, a critical component of the capacitation medium used in in vitro fertilization procedures in mammals. This albumin‐induced Ca 2+ influx is sufficient to activate sAC and stimulate cAMP synthesis independently of HCO 3 − . We further reveal a novel role for albumin, beyond its well‐established function as a cholesterol acceptor, in triggering this rapid Ca 2+ influx and downstream signalling events essential for sperm capacitation. By demonstrating a CatSper‐independent regulatory pathway, we expand the current paradigm of Ca 2+ signalling in sperm physiology.

  PublisherOA PDFDOI

• Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase

  Proceedings of the National Academy of Sciences · 2025-09-24 · 6 citations

  articleOpen access

  Prior to ejaculation, mammalian sperm are stored in the epididymis in a “resting” metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13 C stable isotope labeling in mouse sperm isolated from the cauda epididymis to follow glucose metabolism through central carbon metabolic network before and after sperm activation. As sperm transition from resting to highly activated states, they boost energy yield by increasing flux through glycolysis at the expense of the pentose phosphate pathway. Increased glycolytic activity seems to be achieved via capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the tricarboxylic acid (TCA) cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the flagellum, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase, which also serves to regenerate oxidized nicotinamide adenine dinucleotide (NAD + ) ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm, feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating mouse sperm in glucose.

  PublisherOA PDFDOI

• Biochemical characterization of the full-length isoform of soluble adenylyl cyclase

  Journal of Biological Chemistry · 2025-11-05 · 1 citations

  articleOpen access

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  PublisherDOI

• Sustained soluble adenylyl cyclase (sAC)-generated cAMP is necessary and sufficient for hyperactivated motility in human sperm

  Human Reproduction · 2025-11-17 · 3 citations

  articleOpen accessSenior author

  STUDY QUESTION: How does soluble adenylyl cyclase (sAC)-generated cyclic AMP (cAMP) control hyperactivated motility in human sperm? SUMMARY ANSWER: sAC-generated cAMP rapidly initiates and is required to maintain hyperactivated motility in human sperm. WHAT IS KNOWN ALREADY: Mouse and human sperm devoid of sAC activity (either genetically or pharmacologically) are immotile and do not undergo capacitation; thus, the HCO3--dependent stimulation of sAC and consequent increase in cAMP is responsible for activating basal motility and initiating capacitation in multiple mammalian species. Among the changes sperm undergo during capacitation is acquisition of hyperactivated motility, which is presumed to be essential for male fertility. STUDY DESIGN, SIZE, DURATION: In this study, the kinetics of cAMP generation and motility were assessed in sperm from healthy semen donors with no known fertility issues subjected to capacitating media components (HCO3- and albumin). Controls included cAMP agonists and adenylyl cyclase inhibitors. PARTICIPANTS/MATERIALS, SETTING, METHODS: The motility of sperm purified from donors' semen samples was analyzed by a Computer-Assisted Sperm Analysis (CASA) system, and the intracellular cAMP was quantified using a cAMP ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: HCO3- stimulates sAC-dependent cAMP production and the transition to hyperactivated motility at the earliest times measured. Sperm hyperactivated motility seems to be a reversible process, as maintaining hyperactivated motility requires sustained sAC activation. LIMITATIONS, REASONS FOR CAUTION: The CASA system, used to measure hyperactivated motility, employs snapshot technology; sperm trajectories are observed for only short segments of time. This is an ex vivo study of sperm motility parameters in aqueous solutions. The conditions used were established for successful IVF, and the capacitation-induced hyperactivated motility studied here is proven essential for IVF and positively correlated with in vivo fertilization competence. However, in vivo, ejaculated sperm must navigate through the female reproductive tract, which is lined by viscous mucus, to reach the site of fertilization. Future studies should examine motility behaviors in solutions whose viscosity more accurately reflects the mucus-lined environment of the female reproductive tract. WIDER IMPLICATIONS OF THE FINDINGS: There are two novel findings presented here; that hyperactivation of human sperm occurs early during capacitation and that hyperactivated motility is reversible. These findings raise the possibility that the rapid, sAC-dependent hyperactivated motility allows human sperm to escape the harsh vaginal environment. Its roles modulating sperm motility define sAC as an optimal target for both male and female contraception. Additionally, sAC inhibitors with different off-rates are shown here to be useful tools enabling us to study the kinetics of sAC activation in a physiological context. STUDY FUNDING/COMPETING INTEREST(S): The research was funded by Male Contraceptive Initiative (to J.B. and L.R.L.) and National Institutes of Health via HD113015 and HD111549 (to J.B. and L.R.L.). C.R. was awarded a Male Contraceptive Initiative fellowship. L.R.L. and J.B. are co-inventors of a panel of in vivo, validated sAC inhibitors (patent PCT/US2022/02652) and are co-founders, co-owners, and members of the Board of Directors of Sacyl Pharmaceuticals Inc., which licensed the sAC inhibitors for development into on-demand male contraceptives. C.R. has been a paid consultant to Sacyl Pharmaceuticals Inc. TRIAL REGISTRATION NUMBER: N/A.

  PublisherOA PDFDOI

• Updating the Mechanism of Bicarbonate (HCO3−) Activation of Soluble Adenylyl Cyclase (sAC)

  International Journal of Molecular Sciences · 2025-07-03 · 3 citations

  articleOpen accessSenior author

  Soluble adenylyl cyclase (sAC) is molecularly and biochemically distinct from other mammalian nucleotidyl cyclases. It is uniquely regulated directly by bicarbonate (HCO3−) and calcium (Ca2+) ions and is responsive to physiologic fluctuations in levels of its substrate, adenosine triphosphate (ATP). Our initial in vitro biochemical studies suggested two mechanisms for HCO3−-dependent elevation of sAC activity: increasing catalytic rate and relieving inhibition observed in the presence of supraphysiological levels of substrate, ATP. Structural and mutational studies revealed that HCO3− increases catalytic rate via the disruption of a salt bridge that facilitates productive interactions with the substrate. Here, we demonstrate that the HCO3− stimulation observed under supraphysiological ATP concentrations is due to the mitigation of ATP-dependent acidification. Therefore, we conclude that the sole physiologically relevant mechanism of HCO3− regulation of sAC is through its pH-independent effect facilitating productive substrate binding to the catalytic site.

  PublisherOA PDFDOI

• Cyclic AMP Rescue of Motility in Sperm Devoid of Soluble Adenylyl Cyclase

  International Journal of Molecular Sciences · 2025-02-11 · 4 citations

  articleOpen access

  The second messenger cAMP plays multiple critical roles in the control of sperm functions essential for male fertility, including motility. The enzyme soluble adenylyl cyclase (sAC; ADCY10) was shown genetically and pharmacologically to be the essential source of cAMP mediating many of these functions. Male mice and men with genetic deletions of sAC are infertile, and their sperm are progressively immotile. Pharmacologically, delivery of potent and specific sAC inhibitors to male mice renders them temporarily infertile, and their sperm are similarly immotile. Here, we show that males from a second, independently derived mouse sAC knockout line are also infertile with progressively immotile sperm. We use these mouse models to determine optimal conditions for pharmacologically elevating intracellular cAMP to rescue the sAC null motility defect. We show that cell-permeable cAMP analogs, but not forskolin, rescue the motility defects of sAC deficient sperm, and we demonstrate that 8Br-cAMP is an efficient cAMP analog to rescue motility.

  PublisherDOI

• Sperm meet the elevated energy demands to attain fertilization competence by increasing flux through aldolase

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-10 · 4 citations

  preprintOpen access

  Abstract Prior to ejaculation, sperm are stored in the epididymis in a ‘resting’ metabolic state. Upon ejaculation, sperm must alter their metabolism to generate the energy needed to support the motility and maturation process known as capacitation to reach and fertilize the oocyte. How sperm regulate the capacitation-induced increase in carbon flux is unknown. Here, we use 13 C stable isotope labeling to follow glucose metabolism through sperm central carbon metabolic network before and after sperm activation. We identify regulatory steps which sperm use to alter their metabolic state from resting to highly active. In activated sperm, glucose flux through glycolysis is increased at the expense of the pentose phosphate pathway to increase energy yield. Increased glycolytic activity seems to be due to capacitation-induced stimulation of flux through aldolase. In the mitochondria-containing midpiece, glycolytically generated pyruvate feeds the TCA cycle to further maximize energy yield via oxidative phosphorylation. In the mitochondria-free principal piece of the tail, pyruvate produced from glycolysis is reduced to lactate by lactate dehydrogenase. Reduction to lactate regenerates oxidized NAD + ensuring a sufficient supply to support glycolysis. The resultant lactate is at least partially secreted. Finally, we find evidence that there is an as yet unknown endogenous source of energy in sperm feeding the upregulation of TCA cycle intermediates. These studies provide the most complete picture of the metabolic shift which occurs in capacitating sperm. Significance statement A rapid switch from a quiescent to a high energy-demanding state during ejaculation is essential for sperm to reach and fertilize the oocyte. Somatic cells also undergo bioenergetic switches from low to very high energy demand. However, because metabolic processes essential for proliferation are going on in parallel, it is difficult to identify the molecular mechanisms regulating the increase in ATP production. This study represents the first complete picture of the metabolic reprogramming that happens in sperm upon ejaculation. Using stable isotope labeling, we identify rate-limiting enzymatic steps and points of regulation directing the changes in metabolic flux. Our sperm metabolic studies allow us to identify conserved mechanisms of metabolic regulation that are crucial for the survival of mammalian cells.

  PublisherOA PDFDOI

• David Garbers and the Birth of cAMP Biology in Mammalian Sperm

  Molecular Reproduction and Development · 2024-10-01 · 3 citations

  reviewOpen access

  Dr. David Garbers made many impactful contributions to science and vastly improved our understanding of sperm biology. In this review, we focus on his identification of a key role for the second messenger cAMP in mammalian sperm. As a graduate student David discovered that sperm motility, which is essential for sperm to fertilize the egg, is under the control of the (at the time) recently identified, prototypical second messenger cAMP. Fast-forwarding to the present, agents which turn off sperm's ability to generate cAMP and block sperm motility are being investigated as potential nonhormonal contraceptives for men and women. Should these efforts prove successful, Dave's discoveries will prove to be the spark which ignited a revolution in human health.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01NS055255

  NIH · $1.5M · 2010

• Comparative studies on the regulation of metabolism during sperm capacitation

  NIH · $5.4M · 2017–2027

• High Throughput screen to identify "first of their kind" activators of ADCY10

  NIH · $2.3M · 2019–2023

• NIH Grant R01HD059913

  NIH · $1.7M · 2014

• Modulating intraocular pressure to treat ocular hypotony and glaucoma

  NIH · $476k · 2015–2017

Frequent coauthors

• Jochen Buck

  University of Chicago

  230 shared

• Raminta Baušytė

  Universidad de Los Andes, Chile

  98 shared

• Rūta Navakauskienė

  Vilnius University

  98 shared

• Edita Kazėnaitė

  98 shared

• Diana Ramašauskaitė

  Vilnius University

  98 shared

• Melanie Balbach

  University of Chicago

  89 shared

• Pablo E. Visconti

  Consejo Nacional de Investigaciones Científicas y Técnicas

  61 shared

• Ana Romarowski

  Universidad Maimónides

  58 shared

Education

• PhD

  Cold Spring Harbor Laboratory

  1989

• BS

  Cornell University

  1983