PMID- 28332205
OWN - NLM
STAT- MEDLINE
DCOM- 20180326
LR  - 20181222
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 595
IP  - 13
DP  - 2017 Jul 1
TI  - Evidence that 5-HT stimulates intracellular Ca(2+) signalling and activates 
      pannexin-1 currents in type II cells of the rat carotid body.
PG  - 4261-4277
LID - 10.1113/JP273473 [doi]
AB  - KEY POINTS: 5-HT is a neuromodulator released from carotid body (CB) 
      chemoreceptor (type I) cells and facilitates the sensory discharge following 
      chronic intermittent hypoxia (CIH). In the present study, we show that, in 
      addition to type I cells, adjacent glial-like type II cells express functional, 
      ketanserin-sensitive 5-HT(2) receptors, and their stimulation increases 
      cytoplasmic Ca(2+) derived from intracellular stores. In type II cells, 5-HT 
      activated a ketanserin-sensitive inward current (I(5-HT) ) that was similar to 
      that (I(UTP) ) activated by the P2Y2R agonist, UTP. As previously shown for 
      I(UTP) , I(5-HT) was inhibited by BAPTA-AM and carbenoxolone (5 mum), a putative 
      blocker of ATP-permeable pannexin (Panx)-1 channels; I(UTP) was reversibly 
      inhibited by the specific Panx-1 mimetic peptide channel blocker, (10) Panx 
      peptide. Paracrine stimulation of type II cells by 5-HT, leading to ATP release 
      via Panx-1 channels, may contribute to CB excitability, especially in 
      pathophysiological conditions associated with CIH (e.g. obstructive sleep 
      apnoea). ABSTRACT: Carotid body (CB) chemoreceptor (type I) cells can synthesize 
      and release 5-HT and increased autocrine-paracrine 5-HT(2) receptor signalling 
      contributes to sensory long-term facilitation during chronic intermittent hypoxia 
      (CIH). However, recent studies suggest that adjacent glial-like type II cells can 
      respond to CB paracrine signals by elevating intracellular calcium (Delta[Ca(2+) ](i) 
      ) and activating carbenoxolone-sensitive, ATP-permeable, pannexin (Panx)-1-like 
      channels. In the present study, using dissociated rat CB cultures, we found that 
      5-HT induced Delta[Ca(2+) ](i) responses in a subpopulation of type I cells, as well 
      as in most ( approximately 67%) type II cells identified by their sensitivity to the P2Y2 
      receptor agonist, UTP. The 5-HT-induced Ca(2+) response in type II cells was 
      dose-dependent (EC(50)  approximately 183 nm) and largely inhibited by the 5-HT(2A) receptor 
      blocker, ketanserin (1 mum), and also arose mainly from intracellular stores. 5-HT 
      also activated an inward current (I(5-HT) ) in type II cells (EC(50)  approximately 200 nm) 
      that was reversibly inhibited by ketanserin (1-10 nm), the Ca(2+) chelator 
      BAPTA-AM (5 mum), and low concentrations of carbenoxolone (5 mum), a putative 
      Panx-1 channel blocker. I(5-HT) reversed direction at approximately -11 mV and 
      was indistinguishable from the UTP-activated current (I(UTP) ). Consistent with a 
      role for Panx-1 channels, I(UTP) was reversibly inhibited by the specific Panx-1 
      mimetic peptide blocker (10) Panx (100 mum), although not by its scrambled control 
      peptide ((sc) Panx). Because ATP is an excitatory CB neurotransmitter, it is 
      possible that the contribution of enhanced 5-HT signalling to the increased 
      sensory discharge during CIH may occur, in part, by a boosting of ATP release 
      from type II cells via Panx-1 channels.
CI  - (c) 2017 The Authors. The Journal of Physiology (c) 2017 The Physiological Society.
FAU - Murali, Sindhubarathi
AU  - Murali S
AD  - Department of Biology, McMaster University, Hamilton, Ontario, Canada.
FAU - Zhang, Min
AU  - Zhang M
AD  - Department of Biology, McMaster University, Hamilton, Ontario, Canada.
FAU - Nurse, Colin A
AU  - Nurse CA
AUID- ORCID: 0000-0002-9514-858X
AD  - Department of Biology, McMaster University, Hamilton, Ontario, Canada.
LA  - eng
GR  - MOP 142469/CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170425
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Connexins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Purinergic P2Y Receptor Antagonists)
RN  - 0 (Serotonin Receptor Agonists)
RN  - 0 (pannexin 1, rat)
RN  - 333DO1RDJY (Serotonin)
RN  - 526U7A2651 (Egtazic Acid)
RN  - K22DDW77C0 (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)
RN  - MM6384NG73 (Carbenoxolone)
SB  - IM
MH  - *Action Potentials
MH  - Animals
MH  - *Calcium Signaling
MH  - Carbenoxolone/pharmacology
MH  - Carotid Body/cytology/*metabolism
MH  - Cells, Cultured
MH  - Chemoreceptor Cells/drug effects/*metabolism
MH  - Connexins/antagonists & inhibitors/*metabolism
MH  - Egtazic Acid/analogs & derivatives/pharmacology
MH  - Nerve Tissue Proteins/antagonists & inhibitors/*metabolism
MH  - Purinergic P2Y Receptor Antagonists/pharmacology
MH  - Rats
MH  - Rats, Wistar
MH  - Serotonin/*pharmacology
MH  - Serotonin Receptor Agonists/*pharmacology
PMC - PMC5491882
OTO - NOTNLM
OT  - 5-HT2 receptors
OT  - ketanserin
OT  - pannexin-1 channels
EDAT- 2017/03/24 06:00
MHDA- 2018/03/27 06:00
PMCR- 2018/07/01
CRDT- 2017/03/24 06:00
PHST- 2016/09/14 00:00 [received]
PHST- 2017/03/16 00:00 [accepted]
PHST- 2017/03/24 06:00 [pubmed]
PHST- 2018/03/27 06:00 [medline]
PHST- 2017/03/24 06:00 [entrez]
PHST- 2018/07/01 00:00 [pmc-release]
AID - TJP12347 [pii]
AID - 10.1113/JP273473 [doi]
PST - ppublish
SO  - J Physiol. 2017 Jul 1;595(13):4261-4277. doi: 10.1113/JP273473. Epub 2017 Apr 25.