Novel short isoforms of adenylyl cyclase as negative regulators of cAMP production

Abstract

Here, we cloned a new family of four adenylyl cyclase (AC) splice variants from interleukin-1β (IL-1β)-transdifferentiated vascular smooth muscle cells (VSMCs) encoding short forms of AC8 that we have named "AC8E-H". Using biosensor imaging and biochemical approaches, we showed that AC8E-H isoforms have no cyclase activity and act as dominant-negative regulators by forming heterodimers with other full-length ACs, impeding the traffic of functional units towards the plasma membrane. The existence of these dominant-negative isoforms may account for an unsuspected additional degree of cAMP signaling regulation. It also reconciles the induction of an AC in transdifferentiated VSMCs with the vasoprotective influence of cAMP. The generation of alternative splice variants of ACs may constitute a generalized strategy of adaptation to the cell's environment whose scope had so far been ignored in physiological and/or pathological contexts.

A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission

“…Upon heterodimerization, this may result in activation or dominant-negative inhibition, dependent on AC isoform composition of the tip domain and changing environmental stimuli to fine-tune cAMP levels. Dominant-negative heterodimer formation has previously been described for invertebrate soluble guanylate cyclase (GC) 70 , mammalian AC8 in vascular smooth muscle cells 71 and also ESAG4 of trypanosomes 33 . In agreement with the model, AC isoform diversity and non-redundancy at the flagellar tip 7 and differential expression of transcripts encoding AC isoforms in trypanosomes colonizing midgut, cardia or salivary glands 36 , 37 have been reported.…”

Cellular context shapes cyclic nucleotide signaling in neurons through multiple levels of integration

“…Such negative trend was not observed in pyramidal cortical neurons showing that a buffering effect did not affect the responses in these conditions (Castro et al, 2013). However, the buffering effect was clearly observed in vascular smooth muscle cells, with a statistically lower cAMP response in the cells expressing the biosensor at the highest level (Figure 5 in (Vallin et al, 2018)). Simulations using a model built from our biosensor recordings showed that this buffering effect is negligible in striatal medium-sized spiny neurons, in relation with the high turn-over of cAMP in this neuronal type (Yapo et al, 2017).…”

A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission

“…6f). Dominant-negative heterodimer formation has previously been described for invertebrate soluble guanylate cyclase (GC) 85 , mammalian AC8 in vascular smooth muscle cells 86 and also ESAG4 of trypanosomes 31 .…”