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Adenylyl cyclase 9: Fundamental change of regulation in vertebrates and gene sub-functionalization after teleost-specific whole-genome duplication.

Overview

Authors: Ferenc A Antoni1, Julie Mazzolini1, Heather McClafferty1, Zhiaho Chen1, Laura Szalai2, Cristina Xia1, Sahad Iqbal1, Martin Denvir3, András Balla2, Dirk Sieger1, Michael J Shipston1, Paul Skehel1
ORCID iDs: Ferenc A Antoni
  1. Centre for Discovery Brain Sciences, Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH9 9XD, Scotland, UK
  2. Department of Physiology, Semmelweis University, 1094 Budapest, Hungary
  3. Cardiovascular Research Centre, Institute of Neuroscience and Cardiovascular Research, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK
Institutions: University of Edinburgh (United Kingdom); Semmelweis University (Hungary)
Journal: iScience, volume 29, issue 7, article 116562
Dates: received 9 January 2026; accepted 9 June 2026; published online 7 July 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI 10.1016/j.isci.2026.116562 · PMID 42438824 · PMCID PMC13356687 · OpenAlex W7167584744
Open access: gold, a free copy (OpenAlex)
Status: code on request
Categories: genetics / omics (modality), other (organism), zebrafish (organism), cellular / molecular (subfield)
Methods: Statistics, Evoked potentials
Keywords: adenylyl cyclase, auto-inhibition, G protein coupled receptors, whole genome duplication, zebrafish, medaka
Topic: Developmental Biology and Gene Regulation (Molecular Biology, Biochemistry, Genetics and Molecular Biology), according to OpenAlex
Funding: UK Research and Innovation Medical Research Council (MR/R010668, MR/V012290/1); University of Edinburgh; University of Sheffield
Citations: not cited yet (Europe PMC); 54 references in the paper

Abstract

In mammals, transmembrane adenylyl cyclase 9 (AC9) is resistant to regulation by cell surface receptors coupled to heterotrimeric G proteins. A major facet of this resistance is auto-inhibition—in the presence of activated Gsa, AC9 is inhibited by its C-terminal domain. Here, we examined the evolution of this seemingly paradoxical control mechanism. The hallmarks of auto-inhibition are apparent in all vertebrates; none are found in invertebrates. Teleost-specific whole genome duplication (TGD) resulted in adcy9 ohnologs, one of which lacked the hallmarks of auto-inhibition, which was confirmed in functional assays. The tissue distributions of the adcy9 ohnologs in teleost species pointed to their sub-functionalization. Auto-inhibited adcy9 was largely restricted to the brain, indicating a significant role in brain function. We document a fundamental change in the regulation of the enzymatic activity of AC9 and the potency of TGD to meet an adaptational challenge through functionally diversified ohnologs.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

No dataset and no data link were found in the paper.

Data and code availability

The results of all database searches are shown in the supplement.

Excel files of the biosensor recordings reporting cAMP levels are attached as Table S2.

The western blot image shown is uncropped except for the position of the size markers.

The coding sequence of zebrafish adcy9a has been registered as adenylyl_cyclase_9a GenBank: PX511566 (https://www.ncbi.nlm.nih.gov/nuccore/PX511566).

This paper does not report original code.

Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 6 keywords, 3 funders, 53 references.

Cite

This paper

Antoni, F. A., Mazzolini, J., McClafferty, H., Chen, Z., Szalai, L., Xia, C., Iqbal, S., Denvir, M., Balla, A., Sieger, D., Shipston, M. J., & Skehel, P. (2026). Adenylyl cyclase 9: Fundamental change of regulation in vertebrates and gene sub-functionalization after teleost-specific whole-genome duplication. iScience, 29(7), 116562. https://doi.org/10.1016/j.isci.2026.116562

BibTeX

@article{antoni2026adenylyl,
author = {Antoni, Ferenc A and Mazzolini, Julie and McClafferty, Heather and Chen, Zhiaho and Szalai, Laura and Xia, Cristina and Iqbal, Sahad and Denvir, Martin and Balla, András and Sieger, Dirk and Shipston, Michael J and Skehel, Paul},
title = {{Adenylyl cyclase 9: Fundamental change of regulation in vertebrates and gene sub-functionalization after teleost-specific whole-genome duplication}},
journal = {iScience},
year = {2026},
month = jul,
volume = {29},
number = {7},
pages = {116562},
publisher = {Elsevier},
issn = {2589-0042},
doi = {10.1016/j.isci.2026.116562},
url = {https://doi.org/10.1016/j.isci.2026.116562},
pmid = {42438824},
pmcid = {PMC13356687}
}

RIS

TY - JOUR
AU - Antoni, Ferenc A
AU - Mazzolini, Julie
AU - McClafferty, Heather
AU - Chen, Zhiaho
AU - Szalai, Laura
AU - Xia, Cristina
AU - Iqbal, Sahad
AU - Denvir, Martin
AU - Balla, András
AU - Sieger, Dirk
AU - Shipston, Michael J
AU - Skehel, Paul
TI - Adenylyl cyclase 9: Fundamental change of regulation in vertebrates and gene sub-functionalization after teleost-specific whole-genome duplication
T2 - iScience
J2 - iScience
PY - 2026
DA - 2026/07/07
VL - 29
IS - 7
SP - 116562
SN - 2589-0042
PB - Elsevier
DO - 10.1016/j.isci.2026.116562
UR - https://doi.org/10.1016/j.isci.2026.116562
LA - en
ER -

CSL-JSON

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