Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2

Meigh, Louise; Hussain, Naveed; Mulkey, Daniel K.; Dale, Nicholas

doi:10.7554/elife.04249

Cited by 36 publications

(72 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Meigh et al. , , ). The parental HeLa cells do not load with dye in response to either a CO 2 stimulus or removal of extracellular Ca 2+ following transfection with an empty vector (Meigh et al.…”

Section: Resultsmentioning

confidence: 98%

“…The parental HeLa cells do not load with dye in response to either a CO 2 stimulus or removal of extracellular Ca 2+ following transfection with an empty vector (Meigh et al. , , ). The parental HeLa cells thus have no endogenous hemichannels or CO 2 sensitivity and are an ideal expression system for Cx26 and its mutant subunits.…”

Section: Resultsmentioning

confidence: 99%

“…Recently we reported that the KID syndrome mutation A88V abolished the sensitivity of Cx26 to CO 2 (Meigh et al. ). This mutation acted in a dominant fashion to abolish the CO 2 sensitivity of wild‐type Cx26 hemichannels (Meigh et al.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the patient carrying this mutation experienced central apnea and disordered breathing (Meigh et al. ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

et al. 2016

Self Cite

View full text Add to dashboard Cite

Connexin26 (Cx26) mutations underlie human pathologies ranging from hearing loss to keratitis ichthyosis deafness (KID) syndrome. Cx26 hemichannels are directly gated by CO 2 and contribute to the chemosensory regulation of breathing. The KID syndrome mutation A88V is insensitive to CO 2, and has a dominant negative action on the CO 2 sensitivity of Cx26WT hemichannels, and reduces respiratory drive in humans. We have now examined the effect of further human mutations of Cx26 on its sensitivity to CO 2 . Mutated Cx26 subunits, carrying one of A88S, N14K, N14Y, M34T, or V84L, were transiently expressed in HeLa cells. The CO 2‐dependence of hemichannel activity, and their ability to exert dominant negative actions on cells stably expressing Cx26WT, was quantified by a dye‐loading assay. The KID syndrome mutation, N14K, abolished the sensitivity of Cx26 to CO 2. Both N14Y and N14K exerted a powerful dominant negative action on the CO 2 sensitivity of Cx26WT. None of the other mutations (all recessive) had a dominant negative action. A88S shifted the affinity of Cx26 to slightly higher levels without reducing its ability to fully open to CO 2. M34T did not change the affinity of Cx26 for CO 2 but reduced its ability to open in response to CO 2. V84L had no effect on the CO 2‐sensitivity of Cx26. Some pathological mutations of Cx26 can therefore alter the CO 2 sensitivity of Cx26 hemichannels. The loss of CO 2 sensitivity could contribute to pathology and consequent reduced respiratory drive could be an unrecognized comorbidity of these pathologies.

show abstract

Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Interestingly, the patient carrying this mutation experienced central apnea and disordered breathing (Meigh et al. ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although the majority of evidences suggesting that purinergic signaling contributes to RTN chemoreception were obtained from anesthetized animals or more reduced preparations , recent evidence suggests that CO2-evoked ATP release may also contribute to breathing in unanesthetized humans during quiet sleep (Meigh et al, 2014). Therefore, a goal of this study is to determine if purinergic signaling contributes to central chemoreception in awake animals.…”

Section: Introductionmentioning

confidence: 99%

O bloqueio purinérgico no núcleo retrotrapezóide (RTN) atenua as respostas respiratórias promovidas pela ativação dos quimiorreflexos central e periférico em ratos.

Barna¹

View full text Add to dashboard Cite

Ao Prof. Dr. Thiago dos Santos Moreira que me agraciou com seus ensinamentos, paciência e tempo para que eu me desenvolvesse profissionalmente em seu laboratório e na vida. À Profa. Dra. Ana Carolina T. Takakura pelo apoio e dedicação ao meu projeto.Ao colaborador e surpevisor Prof. Dr. Daniel K. Mulkey o qual me acolheu em seu laboratório e promoveu minha experiência na pesquisa nos Estados Unidos.Aos Prof. Sara Joyce Shammah-Lagnado e Dr. Martin Andreas Metzger e à Ana Maria P. Campos que sempre foram mestres para mim no auxílio da minha formação, me auxiliando em todas minhas dúvidas.Aos meus pais Gilmar e Vanilda, irmão Bernardo, meu marido Julio e sua família que estiveram comigo em todos os momentos, me incentivando a seguir em frente e me apoiando no que fosse preciso, sem os quais eu jamais teria chegado até aqui.À todos os meus amigos, em especial Ana Paula M. Vivas e Luciene A. T. de Souza, e familiares que perceberam minha ausência em muitos momentos importantes mas sempre me incentivaram a seguir em frente.Aos meus grandes amigos do ICB Izabela Martina R. R. de Toledo, Karina Thieme, Talita M. Silva e Luiz Marcelo Oliveira dos quais me orgulho e me espelho e que estiveram comigo em todos os momentos me animando e dividindo suas experiências.Aos meus colegas do ICB pelas experiências divididas no laboratório, durante as disciplinas e em especial aos cursos de verão, os quais me deram a chance de colocar a prova meus conhecimentos e ter a maravilhosa experiência da docência. A respiração é um processo neural essencial para a homeostasia do organismo humano, o qual regula os níveis de O 2 e CO 2 no sangue. Evidências sugerem que o ATP mediando a sinalização purinérgica no bulbo ventrolateral rostral (RVLM) contribui para o controle quimiorrreceptor central e periférico regulando a pressão arterial e a respiração. Dessa maneira, neurônios do núcleo retrotrapezóide (RTN) agem como quimiorreceptores centrais que em parte respondem ao ATP liberado pelo aumento de CO 2 por meio da ativação de receptores P2 ainda desconhecidos, regulando a respiração, e os neurônios catecolaminérgico C1 regulam as respostas de pressão arterial à ativação dos quimiorreceptores periféricos por um mecanismo dependente de receptor P2Y. No entanto, as potenciais contribuições da sinalização purinérgica, no RTN, na função cardiorrespiratória em animais não anestesiados ainda não foram testadas. Neste estudo mostramos que a injeção unilateral de ATP no RTN promoveu aumento da atividade cardiorrespiratória por um mecanismo dependente de receptores P2. Mostramos também que as injeções bilaterais, no RTN, do bloqueador de receptor P2 não específico (PPADS), mas não de receptores específicos P2Y (MRS2179), reduziu a resposta ventilatória à hipercapnia (7% CO 2 ) e hipóxia (8% O 2 ) em ratos não anestesiados. Além disso, a aplicação da adenosina (ADO) no RTN atenuou o aumento da ventilação induzido por hipercapnia in vivo, bem como o disparo dos neurônios in vitro. Estes resultados demonstram que a sinalização mediada por ATP contribui p...

show abstract

Brain H⁺/CO₂ sensing and control by glial cells

Gourine

Dale

2022

Glia

Self Cite

View full text Add to dashboard Cite

Maintenance of constant brain pH is critically important to support the activity of individual neurons, effective communication within the neuronal circuits, and, thus, efficient processing of information by the brain. This review article focuses on how glial cells detect and respond to changes in brain tissue pH and concentration of CO2, and then trigger systemic and local adaptive mechanisms that ensure a stable milieu for the operation of brain circuits. We give a detailed account of the cellular and molecular mechanisms underlying sensitivity of glial cells to H+ and CO2 and discuss the role of glial chemosensitivity and signaling in operation of three key mechanisms that work in concert to keep the brain pH constant. We discuss evidence suggesting that astrocytes and marginal glial cells of the brainstem are critically important for central respiratory CO2 chemoreception—a fundamental physiological mechanism that regulates breathing in accord with changes in blood and brain pH and partial pressure of CO2 in order to maintain systemic pH homeostasis. We review evidence suggesting that astrocytes are also responsible for the maintenance of local brain tissue extracellular pH in conditions of variable acid loads associated with changes in the neuronal activity and metabolism, and discuss potential role of these glial cells in mediating the effects of CO2 on cerebral vasculature.

show abstract

Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2

Cited by 36 publications

References 22 publications

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

O bloqueio purinérgico no núcleo retrotrapezóide (RTN) atenua as respostas respiratórias promovidas pela ativação dos quimiorreflexos central e periférico em ratos.

Brain H⁺/CO₂ sensing and control by glial cells

Contact Info

Product

Resources

About

Connexin26 hemichannels with a mutation that causes KID syndrome in humans lack sensitivity to CO2

Cited by 36 publications

References 22 publications

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro

Altered CO2 sensitivity of connexin26 mutant hemichannels in vitro

O bloqueio purinérgico no núcleo retrotrapezóide (RTN) atenua as respostas respiratórias promovidas pela ativação dos quimiorreflexos central e periférico em ratos.

Brain H+/CO2 sensing and control by glial cells

Contact Info

Product

Resources

About

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Altered CO₂ sensitivity of connexin26 mutant hemichannels in vitro

Brain H⁺/CO₂ sensing and control by glial cells