Members of the KCTD family are major regulators of cAMP signaling

Brian S. Muntean, Subhi Marwari, Xiaona Li, Douglas C. Sloan, Brian D. Young, James A. Wohlschlegel, Kirill A. Martemyanov

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger with an essential role in neuronal function. cAMP synthesis by adenylyl cyclases (AC) is controlled by G protein–coupled receptor (GPCR) signaling systems. However, the network of molecular players involved in the process is incompletely defined. Here, we used CRISPR/Cas9–based screening to identify that members of the potassium channel tetradimerization domain (KCTD) family are major regulators of cAMP signaling. Focusing on striatal neurons, we show that the dominant isoform KCTD5 exerts its effects through an unusual mechanism that modulates the influx of Zn2+ via the Zip14 transporter to exert unique allosteric effects on AC. We further show that KCTD5 controls the amplitude and sensitivity of stimulatory GPCR inputs to cAMP production by Gβγ-mediated AC regulation. Finally, we report that KCTD5 haploinsufficiency in mice leads to motor deficits that can be reversed by chelating Zn2+. Together, our findings uncover KCTD proteins as major regulators of neuronal cAMP signaling via diverse mechanisms.

Original languageEnglish (US)
Article numbere2119237119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number1
StatePublished - Jan 4 2022
Externally publishedYes


  • CAMP
  • GPCR
  • Neuron
  • Striatum
  • Zinc

ASJC Scopus subject areas

  • General


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