Bioinformatic analysis of specificity in signaling that controls smooth muscle tone

Abstract

Abnormal SMC force production is common to diseases including hypertension and asthma. Smooth muscle is phenotypically diverse and variable in its response to signals that regulate force production. We have focused on Myosin phosphatase (MP), the primary effector of SMC relaxation and a key target of signals that regulate SMC force. Variable splicing of Exon24 of the regulatory subunit Mypt1 results in variable expression of a leucine zipper (LZ) motif that is required for NO/cGMP signaling. Here we expanded our investigation of variation in this pathway using bioinformatic analysis of phylogenetic sequence conservation, tissue‐specific expression, and regulatory motifs, placing emphasis on alternative transcripts and LZ motifs. Mypt2 gives rise to numerous muscle subtype‐specific transcripts. Both Mypt2 and the upstream cGMP‐kinase generate mutually exclusive LZ motifs through alternative exons that show variable phylogenetic conservation. While the catalytic subunit of MP is highly conserved, the inhibitory subunits (PPP1R14a‐d) are less well conserved, have inter‐individual variability in sequence (SNPs), and great diversity in expression. These data suggest that variability in the regulatory subunits of MP may determine differences in SMC responses to dilator and constrictor signals between individuals and in disease states. This variability may be informative for drug therapy targeting.