Â鶹´«Ã½É«ÇéƬ

Annual Meeting

The benefits of being an open-minded skeptic

Meet a JBC Herbert Tabor Early Career Investigator Award winner
Brian O'Flynn
March 16, 2022

A common thread in Jacob Rowe’s academic path has been the development of strong scientific principles coupled with a creative flair and open-mindedness.

A B.S. in chemistry from East Carolina University garnered Rowe a toolkit of knowledge but little research experience. A subsequent M.S. at the University of North Carolina Wilmington under the watchful eye of was his introduction to research and where he developed his scientific fundamentals.

Jacob Rowe
Jacob Rowe

Switching to molecular and cellular pharmacology in pursuit of a Ph.D. at the University of Miami landed Rowe in the lab of , a former fine arts major and practicing pharmacologist and biophysicist.

“Dan has always been good at the innovation side of things,” Rowe said. “He likes to stay with the latest and greatest techniques.”

In Isom’s lab, Rowe was encouraged to develop his more creative instincts. “There’s a lot of value in being creative in science,” he said. “You can really expand the type of scientist you are.”

Rowe discovered that a creative flair could function well with the skepticism of a scientist when he began pursuing the concept of proton sensing in G protein–coupled receptors, or GPCRs. Driven by a hypothesis developed with the help of Isom’s informatics platform pHinder (pronounced “finder”), Rowe was tasked with identifying whether a buried cluster of charged residues functioned as a proton sensor for a particular group of GPCRs.

This went against some previously published data suggesting extracellular histidines performed this role. Rowe was skeptical of both, pushing himself tirelessly to confirm beyond a doubt that the lab had, in fact, uncovered a novel mechanism for proton sensing in GPCRs.

“The hypothesis just held up all the way through,” he said. “I learned to believe in the power of computational biology.”

Overlooked buried triad responsible for GPCR proton sensing

G protein–coupled receptors function by relaying extracellular signals into intracellular downstream responses. This process can be complex, with multifaceted functional behavior noted for many different GPCRs.

One such nuance lies in the ability of a subgroup of three GPCRs (GPR4, GPR65 and GPR68) to function in response to their local pH — so-called proton-sensing GPCRs. Their discovery came with hypotheses of mechanism, but these never were explored in depth until Rowe and his colleagues set out to do just that.

The team probed for residues that are likely contributors to proton sensing, using the informatics program pHinder. This identified a triad of buried acidic residues, two aspartic acids (referred to as the DyaD) and a glutamic acid (the apEx), spatially conserved across all three proton-sensing GPCRs. A profiling scheme was developed based on CRISPR-generated libraries of GPCR variants and was combined with GPCR assays to explore the contribution of these residues to the mechanism and evolution of proton sensing in GPCRs.

Their results, as described in in the Journal of Biological Chemistry, confirmed that the triad directly regulates pH sensing. But how does this work? pH titrations in the presence and absence of sodium showed that at high pH, a Na+ ion functions to stabilize the DyaD. A drop in pH leads to protonation and subsequent activation of the receptor. Phylogenetic analysis showed the evolutionary lineage of the triad and pointed to new avenues of biological inquiry.

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition weekly.

Learn more
Brian O'Flynn

Brian O'Flynn is a scientific writer at St. Jude Children's Research Hospital in Memphis.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in People

People highlights or most popular articles

Elucidating how chemotherapy induces neurotoxicity
Award

Elucidating how chemotherapy induces neurotoxicity

Dec. 2, 2024

Andre Nussenzweig will receive the Bert and Natalie Vallee Award at the 2025 ASBMB Annual Meeting, April 12–15 in Chicago.

ASBMB committees welcome new members
Announcement

ASBMB committees welcome new members

Nov. 29, 2024

Committee members serve terms of two to five years, and a number of new members have joined. We also thank those whose terms have ended.

Curiosity turned a dietitian into a lipid scientist
Award

Curiosity turned a dietitian into a lipid scientist

Nov. 27, 2024

Judy Storch will receive the Avanti Award in Lipids at the 2025 ASBMB Annual Meeting, April 12–15 in Chicago.

From receptor research to cancer drug development: The impact of RTKs
Award

From receptor research to cancer drug development: The impact of RTKs

Nov. 26, 2024

Joseph Schlessinger will receive the ASBMB Herbert Tabor Research Award at the 2025 ASBMB Annual meeting, April 12–15 in Chicago.

Awards for Alrubaye and Dutta; Strochlic named ass't dean
Member News

Awards for Alrubaye and Dutta; Strochlic named ass't dean

Nov. 25, 2024

PSA presents Early Achievement Award for Teaching to Adnan Alrubaye. ASIP honors Anindya Dutta with the Rous–Whipple Award. Drexel names Todd Strochlic assistant dean of curricular integration.

In memoriam: Arnis Kuksis
In Memoriam

In memoriam: Arnis Kuksis

Nov. 25, 2024

He was a professor emeritus at the University of Toronto who studied the complex mechanisms dictating lipid metabolism and an ASBMB member for more than 40 years.