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Distinct submembrane localisation compartmentalises cardiac NPR1 and NPR2 signalling to cGMP

Subramanian, Hariharan ; Froese, Alexander ; Jönsson, Peter LU ; Schmidt, Hannes ; Gorelik, Julia and Nikolaev, Viacheslav O. (2018) In Nature Communications 9(1).
Abstract

Natriuretic peptides (NPs) are important hormones that regulate multiple cellular functions including cardiovascular physiology. In the heart, two natriuretic peptide receptors NPR1 and NPR2 act as membrane guanylyl cyclases to produce 3′,5′-cyclic guanosine monophosphate (cGMP). Although both receptors protect from cardiac hypertrophy, their effects on contractility are markedly different, from little effect (NPR1) to pronounced negative inotropic and positive lusitropic responses (NPR2) with unclear underlying mechanisms. Here we use a scanning ion conductance microscopy (SICM) approach combined with Förster resonance energy transfer (FRET)-based cGMP biosensors to show that whereas NPR2 is uniformly localised on the cardiomyocyte... (More)

Natriuretic peptides (NPs) are important hormones that regulate multiple cellular functions including cardiovascular physiology. In the heart, two natriuretic peptide receptors NPR1 and NPR2 act as membrane guanylyl cyclases to produce 3′,5′-cyclic guanosine monophosphate (cGMP). Although both receptors protect from cardiac hypertrophy, their effects on contractility are markedly different, from little effect (NPR1) to pronounced negative inotropic and positive lusitropic responses (NPR2) with unclear underlying mechanisms. Here we use a scanning ion conductance microscopy (SICM) approach combined with Förster resonance energy transfer (FRET)-based cGMP biosensors to show that whereas NPR2 is uniformly localised on the cardiomyocyte membrane, functional NPR1 receptors are found exclusively in membrane invaginations called transverse (T)-tubules. This leads to far-reaching CNP/NPR2/cGMP signals, whereas ANP/NPR1/cGMP signals are highly confined to T-tubular microdomains by local pools of phosphodiesterase 2. This provides a previously unrecognised molecular basis for clearly distinct functional effects engaged by different cGMP producing membrane receptors.

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author
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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
9
issue
1
article number
2446
publisher
Nature Publishing Group
external identifiers
  • scopus:85048947928
  • pmid:29934640
ISSN
2041-1723
DOI
10.1038/s41467-018-04891-5
language
English
LU publication?
yes
id
871ad4a5-27d4-42bf-91e3-c4b9c7cfdedb
date added to LUP
2018-07-04 08:55:00
date last changed
2024-04-15 08:56:36
@article{871ad4a5-27d4-42bf-91e3-c4b9c7cfdedb,
  abstract     = {{<p>Natriuretic peptides (NPs) are important hormones that regulate multiple cellular functions including cardiovascular physiology. In the heart, two natriuretic peptide receptors NPR1 and NPR2 act as membrane guanylyl cyclases to produce 3′,5′-cyclic guanosine monophosphate (cGMP). Although both receptors protect from cardiac hypertrophy, their effects on contractility are markedly different, from little effect (NPR1) to pronounced negative inotropic and positive lusitropic responses (NPR2) with unclear underlying mechanisms. Here we use a scanning ion conductance microscopy (SICM) approach combined with Förster resonance energy transfer (FRET)-based cGMP biosensors to show that whereas NPR2 is uniformly localised on the cardiomyocyte membrane, functional NPR1 receptors are found exclusively in membrane invaginations called transverse (T)-tubules. This leads to far-reaching CNP/NPR2/cGMP signals, whereas ANP/NPR1/cGMP signals are highly confined to T-tubular microdomains by local pools of phosphodiesterase 2. This provides a previously unrecognised molecular basis for clearly distinct functional effects engaged by different cGMP producing membrane receptors.</p>}},
  author       = {{Subramanian, Hariharan and Froese, Alexander and Jönsson, Peter and Schmidt, Hannes and Gorelik, Julia and Nikolaev, Viacheslav O.}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Distinct submembrane localisation compartmentalises cardiac NPR1 and NPR2 signalling to cGMP}},
  url          = {{http://dx.doi.org/10.1038/s41467-018-04891-5}},
  doi          = {{10.1038/s41467-018-04891-5}},
  volume       = {{9}},
  year         = {{2018}},
}