The α2β1 isoform of guanylyl cyclase mediates plasma membrane localized nitric oxide signalling

Bellingham, M. and Evans, T. J. (2007) The α2β1 isoform of guanylyl cyclase mediates plasma membrane localized nitric oxide signalling. Cellular Signalling, 19(10), pp. 2183-2193. (doi: 10.1016/j.cellsig.2007.06.017) (PMID:17643962)

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Nitric oxide (NO) is a mediator of copious biological processes, in many cases through the production of cGMP from the enzyme nitric oxide-sensitive guanylyl cyclase. Natriuretic peptides also elevate cGMP, often with distinct biological effects, raising the issue of how specificity is achieved. Here we show that a recently described α2β1 isoform of guanylyl cyclase is expressed in a number of epithelia, where it is localized to the apical plasma membrane. We measured the functional properties of the α2β1 isoform by utilizing the NO-dependent activation of the ion channel cystic fibrosis transmembrane conductance regulator (CFTR), which occurs by phosphorylation via the membrane-bound type II isoform of cGMP-dependent protein kinase. We found that cGMP generated by NO activation of the α2β1 isoform of guanylyl cyclase is an exceptionally efficient mediator of nitric oxide action on membrane targets, activating CFTR far more effectively than the cytoplasmically located α1β1 guanylyl cyclase isoform. Targeting the α1β1 isoform of guanylyl cyclase to the membrane also dramatically enhanced the effects of nitric oxide on CFTR within the membrane. This was not due to increased enzymatic activity of guanylyl cyclase in a membrane location, but to production of a localised membrane pool of cGMP by membrane-localized NO-dependent guanylyl cyclase that was resistant to degradation by phosphodiesterases. Selective effects of cGMP produced from this enzyme in response to NO are directed at membrane targets and suggest that drugs selectively activating or inhibiting this α2β1 isoform of guanylyl cyclase may have unique pharmacological properties.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Evans, Professor Tom and Bellingham, Dr Michelle
Authors: Bellingham, M., and Evans, T. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Cellular Signalling
Journal Abbr.:Cell Signal
ISSN (Online):1873-3913
Published Online:29 June 2007

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
371591The role of Na+/H+ Exchange Regulatory factor in the actions of nitric oxide at apical epithelial membranesTom EvansBiotechnology and Biological Sciences Research Council (BBSRC)C20042Infection Immunity and Inflammation Life Sciences