A tale of two threonines: myosin phosphatase inhibition and calcium sensitization of smooth muscle

摘要: Smooth muscle (SM) contraction is a dynamic and highly regulated process. The contractile properties of SM are primarily governed by the phosphorylation regulatory light chain (LC20) myosin II. To initiate contraction, an increase in intracellular [Ca2+] activates myosin kinase (MLCK), Ca2+/calmodulin-dependent enzyme. MLCK phosphorylates LC20 on Ser19, resulting through increases ATPase activity cross-bridge cycling. Myosin phosphatase (MLCP) responsible for dephosphorylation (Shirazi et al. 1994). Although primary determinant it balance between MLCP activities that predicates precise activity. Indeed, functions independently Ca2+ can be variety signalling pathways. Inhibition leads to both force development without any changes [Ca2+], phenomenon commonly referred as ‘calcium sensitization’. Once thought possess ‘housekeeping activity’, now known under exquisite control (Grassie 2011). A number studies demonstrate (and hence sensitization) myosin-targeting subunit (MYPT1). several sites MYPT1 have been identified since its discovery decade ago, two threonine residues (i.e. T694 T852, numbering mouse isoform) most extensively studied context sensitization. Experimental evidence suggests stimulation agonists elicits variable degrees sensitization depending agonist used employed. These responses associated with degree variability regarding nature stoichiometry phosphorylation. Much debate has directed toward physiological importance at inhibitory residues. relevance T852 approached laboratories recent past. Currently, directly inhibit towards whereas believed cause dissociation from and/or directly. In this issue Journal Physiology, Chen colleagues (2015) examine phosphorylations bladder detrusor SM. In completing assessment, authors generate novel knockin mice (namely heterozygous T694A/– T694A/+ along homozygous T852A null animals). not specific focus study, omphalocele phenotype was coincidently found either T694A or Rho-associated (ROCK) dependency. Moreover, authors’ examinations confirm individual unique roles during regard, mutation significantly sustained well while had no significant effect maximal little maintenance. study also supports presence constitutive mechanism which contributes maintenance via T694. findings offer confirmation vitro data suggested inhibited did (Khasnis 2014). An additional intriguing reported absence status attenuation observed upon exposure ROCK inhibitors. An emergent precept tone embraces cytoskeletal reorganization contributing process operates regulation (Walsh & Cole, 2013). observations provided congruent acting enhance connections actin cytoskeleton, plasma membrane extracellular matrix augment transmission. tissue, agonist-induced appears apparent role regulating responses. One addressed namely dual adjacent S693/T694 S851/T852 dependent relative (T) disinhibitory (S) 2012). Future investigations may provide illumination how cross-talk cyclic nucleotide pathways dictates force. does limitations (e.g. lack adult tissues animals), these interesting shed new function MYPT1. all likelihood, (especially viable T852A) will appreciable investigators’ examination various beds processes. SM display diverse phenotypes functional mechanisms regulate development. However, our understanding operating modulate still incomplete. Obviously, complex involving multiple allow subtle differentiations achieved.