PMID- 35862456
OWN - NLM
STAT- MEDLINE
DCOM- 20220725
LR  - 20220907
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 30
DP  - 2022 Jul 26
TI  - Activity-dependent endoplasmic reticulum Ca(2+) uptake depends on Kv2.1-mediated 
      endoplasmic reticulum/plasma membrane junctions to promote synaptic transmission.
PG  - e2117135119
LID - 10.1073/pnas.2117135119 [doi]
LID - e2117135119
AB  - The endoplasmic reticulum (ER) forms a continuous and dynamic network throughout 
      a neuron, extending from dendrites to axon terminals, and axonal ER dysfunction 
      is implicated in several neurological disorders. In addition, tight junctions 
      between the ER and plasma membrane (PM) are formed by several molecules including 
      Kv2 channels, but the cellular functions of many ER-PM junctions remain unknown. 
      Recently, dynamic Ca(2+) uptake into the ER during electrical activity was shown 
      to play an essential role in synaptic transmission. Our experiments demonstrate 
      that Kv2.1 channels are necessary for enabling ER Ca(2+) uptake during electrical 
      activity, as knockdown (KD) of Kv2.1 rendered both the somatic and axonal ER 
      unable to accumulate Ca(2+) during electrical stimulation. Moreover, our 
      experiments demonstrate that the loss of Kv2.1 in the axon impairs synaptic 
      vesicle fusion during stimulation via a mechanism unrelated to voltage. Thus, our 
      data demonstrate that a nonconducting role of Kv2.1 exists through its binding to 
      the ER protein VAMP-associated protein (VAP), which couples ER Ca(2+) uptake with 
      electrical activity. Our results further suggest that Kv2.1 has a critical 
      function in neuronal cell biology for Ca(2+) handling independent of voltage and 
      reveals a critical pathway for maintaining ER lumen Ca(2+) levels and efficient 
      neurotransmitter release. Taken together, these findings reveal an essential 
      nonclassical role for both Kv2.1 and the ER-PM junctions in synaptic 
      transmission.
FAU - Panzera, Lauren C
AU  - Panzera LC
AUID- ORCID: 0000-0001-8519-039X
AD  - Department of Biology, Dartmouth College, Hanover, NH 03755.
FAU - Johnson, Ben
AU  - Johnson B
AD  - Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 
      80523.
FAU - Quinn, Josiah A
AU  - Quinn JA
AUID- ORCID: 0000-0002-8852-4006
AD  - Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 
      80523.
FAU - Cho, In Ha
AU  - Cho IH
AUID- ORCID: 0000-0002-1404-7681
AD  - Department of Biology, Dartmouth College, Hanover, NH 03755.
FAU - Tamkun, Michael M
AU  - Tamkun MM
AUID- ORCID: 0000-0002-0455-6167
AD  - Department of Biomedical Sciences, Colorado State University, Fort Collins, CO 
      80523.
FAU - Hoppa, Michael B
AU  - Hoppa MB
AUID- ORCID: 0000-0003-2340-0915
AD  - Department of Biology, Dartmouth College, Hanover, NH 03755.
LA  - eng
GR  - P20 GM113132/GM/NIGMS NIH HHS/United States
GR  - F31 NS110192/NS/NINDS NIH HHS/United States
GR  - R01 NS112365/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220721
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Shab Potassium Channels)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/metabolism
MH  - Calcium Signaling
MH  - Cell Membrane/metabolism
MH  - *Endoplasmic Reticulum/metabolism
MH  - Neurons/metabolism
MH  - *Shab Potassium Channels/metabolism
MH  - Synaptic Transmission
PMC - PMC9335237
OTO - NOTNLM
OT  - Kv2
OT  - calcium
OT  - endoplasmic reticulum
OT  - exocytosis
OT  - synaptic transmission
COIS- The authors declare no competing interest.
EDAT- 2022/07/22 06:00
MHDA- 2022/07/26 06:00
PMCR- 2022/07/21
CRDT- 2022/07/21 13:54
PHST- 2022/07/21 13:54 [entrez]
PHST- 2022/07/22 06:00 [pubmed]
PHST- 2022/07/26 06:00 [medline]
PHST- 2022/07/21 00:00 [pmc-release]
AID - 202117135 [pii]
AID - 10.1073/pnas.2117135119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2117135119. doi: 
      10.1073/pnas.2117135119. Epub 2022 Jul 21.