RNA splicing in regulation of nitric oxide receptor soluble guanylyl cyclase

Abstract

Soluble guanylyl cyclase (sGC) is a key protein in the nitric oxide (NO)/-cGMP signaling pathway. sGC activity is involved in a number of important physiological processes including smooth muscle relaxation, neurotransmission and platelet aggregation and adhesion. Regulation of sGC expression and activity emerges as a crucial factor in control of sGC function in normal and pathological conditions. Recently accumulated evidence strongly indicates that the regulation of sGC expression is a complex process modulated on several levels including transcription, post-transcriptional regulation, translation and protein stability. Presently our understanding of mechanisms governing regulation of sGC expression remains very limited and awaits systematic investigation. Among other ways, the expression of sGC subunits is modulated at the levels of mRNA abundance and transcript diversity. In this review we summarize available information on different mechanisms (including transcriptional activation, mRNA stability and alternative splicing) involved in the modulation of mRNA levels of sGC subunits in response to various environmental clues. We also summarize and cross-reference the information on human sGC splice forms available in the literature and in genomic databases. This review highlights the fact that the study of the biological role and regulation of sGC splicing will bring new insights to our understanding of NO/cGMP biology.

Nitric Oxide and Heat Shock Protein 90 Activate Soluble Guanylate Cyclase by Driving Rapid Change in Its Subunit Interactions and Heme Content

“…4, A and B). Interestingly, the predominant form of sGC-␣1 expressed in the RFL-6 cells was a truncated splice variant of 52 kDa, probably similar to the ⌬1-239 splice variant that is expressed in BE2 neuroblastoma cells and in lung tissue, which is missing a portion of the ␣ subunit N-terminal regulatory domain (19,20). The mass distribution of ⌬1-239 sGC-␣1 in the cell supernatant was broad and similar to that of the sGC-␤1 subunit, consistent with the truncated sGC-␣1 subunit and the sGC-␤1 subunit still being able to combine and form an active heterodimer in cells (19,20).…”

Alternative splicing impairs soluble guanylyl cyclase function in aortic aneurysm

“…Alternative splicing of ␣1 and ␤1 sGC can potentially affect the composition, abundance, and functional properties of sGC protein isoforms expressed in blood vessels. Previous studies demonstrated the expression of human sGC splice forms in cell culture models (42). To investigate whether ␣1 and ␤1 sGC splice forms are expressed in human vascular tissue, we obtained aortic specimens from donors deceased from causes unrelated to aortic dysfunction (Capital Biosciences).…”

“…β1-iso 4 (β1Δ 68Ω643) [42] βCAT CC β -PAS HNOX 392 β1-Tr4 βCAT CC β -PAS HNOX β1-Tr5 β1-iso 5 (β1Δ 33) [42] Protein isoform*:…”

“…Several molecular mechanisms were implicated in downregulation of sGC expression and activity in vascular disease, including inhibition of transcription (1,33,34,39,47), destabilization of mRNA (22), and protein degradation in increased oxidative environment (3,9,14). Systematic analysis of the NCBI nucleotide database identifies seven alternatively spliced transcripts for GUCY1A3 gene of the ␣1 subunit (␣1-Tr1 to ␣1-Tr7) and six splice transcripts for the GUCY1B3 gene of the ␤1 subunit (␤1-Tr1 to ␤1-Tr6) (42). In addition to canonical full-length ␣1 (isoform A) and ␤1 (isoform 2) subunits, three more ␣1 protein isoforms (isoforms B, C, D) and five more ␤1 isoforms (isoforms 1, 3, 4, 5, 6) are predicted to be encoded by these transcripts.…”

Hypoxia induces downregulation of soluble guanylyl cyclase β1 by miR-34c-5p

“…The nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cGMP pathway has been implicated in a variety of biological processes, such as vasodilatation, inhibition of platelet aggregation and leukocyte adhesion, neuromodulation and neurotransmission (Sharina et al, 2003;Sharina et al, 2011). To mediate these effects, endogenous and exogenous NO binds to the ferrous iron of sGC heme prosthetic group, triggering a conformational change of sGC followed by the activation of the sGC enzyme.…”