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  • Pantazis, AntoniosLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten,Univ Calif Los Angeles, CA 90095 USA (författare)

Tracking the motion of the K(V)1.2 voltage sensor reveals the molecular perturbations caused by ade novomutation in a case of epilepsy

  • Artikel/kapitelEngelska2020

Förlag, utgivningsår, omfång ...

  • WILEY,2020
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:liu-170559
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-170559URI
  • https://doi.org/10.1113/JP280438DOI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Funding Agencies|NIH/NHLBIUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [R01HL134346]; NIH/NIGMSUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of General Medical Sciences (NIGMS) [R35GM131896]; American Heart Association (National Centre)American Heart Association [14SDG20300018, 17POST33670046]; Knut and Alice Wallenberg FoundationKnut & Alice Wallenberg Foundation; Science for Life Laboratory
  • Key points K(V)1.2 channels, encoded by theKCNA2gene, regulate neuronal excitability by conducting K(+)upon depolarization. A newKCNA2missense variant was discovered in a patient with epilepsy, causing amino acid substitution F302L at helix S4, in the K(V)1.2 voltage-sensing domain. Immunocytochemistry and flow cytometry showed that F302L does not impair KCNA2 subunit surface trafficking. Molecular dynamics simulations indicated that F302L alters the exposure of S4 residues to membrane lipids. Voltage clamp fluorometry revealed that the voltage-sensing domain of K(V)1.2-F302L channels is more sensitive to depolarization. Accordingly, K(V)1.2-F302L channels opened faster and at more negative potentials; however, they also exhibited enhanced inactivation: that is, F302L causes both gain- and loss-of-function effects. Coexpression of KCNA2-WT and -F302L did not fully rescue these effects. The probands symptoms are more characteristic of patients with loss ofKCNA2function. Enhanced K(V)1.2 inactivation could lead to increased synaptic release in excitatory neurons, steering neuronal circuits towards epilepsy. An exome-based diagnostic panel in an infant with epilepsy revealed a previously unreportedde novomissense variant inKCNA2, which encodes voltage-gated K(+)channel K(V)1.2. This variant causes substitution F302L, in helix S4 of the K(V)1.2 voltage-sensing domain (VSD). F302L does not affect KCNA2 subunit membrane trafficking. However, it does alter channel functional properties, accelerating channel opening at more hyperpolarized membrane potentials, indicating gain of function. F302L also caused loss of K(V)1.2 function via accelerated inactivation onset, decelerated recovery and shifted inactivation voltage dependence to more negative potentials. These effects, which are not fully rescued by coexpression of wild-type and mutant KCNA2 subunits, probably result from the enhancement of VSD function, as demonstrated by optically tracking VSD depolarization-evoked conformational rearrangements. In turn, molecular dynamics simulations suggest altered VSD exposure to membrane lipids. Compared to other encephalopathy patients withKCNA2mutations, the proband exhibits mild neurological impairment, more characteristic of patients withKCNA2loss of function. Based on this information, we propose a mechanism of epileptogenesis based on enhanced K(V)1.2 inactivation leading to increased synaptic release preferentially in excitatory neurons, and hence the perturbation of the excitatory/inhibitory balance of neuronal circuits.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Kaneko, MakiChildrens Hosp, CA 90027 USA; Childrens Hosp Los Angeles, CA 90027 USA (författare)
  • Angelini, MarinaUniv Calif Los Angeles, CA 90095 USA (författare)
  • Steccanella, FedericaUniv Calif Los Angeles, CA 90095 USA (författare)
  • Westerlund, Annie M.KTH Royal Inst Technol, Sweden (författare)
  • Lindström, SarahLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)sarli19 (författare)
  • Nilsson, MichelleLinköpings universitet,Avdelningen för neurobiologi,Medicinska fakulteten(Swepub:liu)micni31 (författare)
  • Delemotte, LucieKTH Royal Inst Technol, Sweden (författare)
  • Saitta, Sulagna C.Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA (författare)
  • Olcese, RiccardoUniv Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA; Univ Calif Los Angeles, CA 90095 USA (författare)
  • Linköpings universitetAvdelningen för neurobiologi (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Journal of Physiology: WILEY598:22, s. 5245-52690022-37511469-7793

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