G-protein and protein kinase A signaling networks control contractility and calcium signaling in the Caenorhabditis elegans spermatheca

Abstract

Correct regulation of contractility and dilation in biological tubes is critical for the function of the reproductive, cardiovascular, and other systems. Dysregulation of the signaling networks that control actomyosin contractility can result in diseases such as cardiovascular diseases and asthma. The reproductive system of the hermaphroditic nematode C. elegans contains a contractile tube of myoepithelial cells known as the spermatheca. The spermatheca stores sperm and is the site of oocyte fertilization. Regulated contraction of the spermatheca pushes the embryo into the uterus. These contractions are dependent on actin and myosin and are in part regulated by Ca2+ signaling through the phospholipase PLC-1, which mediates Ca2+ release from the ER. Here I describe the roles of many genes in the regulation of calcium release and contractility in the C. elegans spermatheca, including the G-protein alpha subunit GSA-1/Gs, and its downstream effectors, the catalytic subunit KIN-1/PKA-C and the regulatory subunit KIN-2/PKA-R of protein kinase A, and G-protein alpha subunit GOA-1/Go. I discuss regulators of this pathway, including the phosphodiesterase PDE-6, the phospholipase PLC-1, and possible upstream regulators such as G-protein coupled receptors (GPCR), the G-protein regulators GPR-1 and GPR-2, and the scaffolding protein ERM-1. Without GSA-1/ Gs or KIN-1/PKA-C, calcium is not released, and oocytes become trapped in the spermatheca. Conversely, when PKA is activated through a gain of function allele in GSA-1 (GSA-1(GF)) or by depletion of KIN-2/PKA-R, Ca2+ is increased, and waves of Ca2+ travel across the spermatheca even in the absence of oocyte entry. In the sp-ut valve, loss of GSA-1/ Gs or KIN-1/PKA-C results in sustained, high levels of Ca2+ and a loss of coordination between the spermathecal bag and sp-ut valve. Additionally, I show that depleting phosphodiesterase PDE-6 levels alters contractility and Ca2+ dynamics in the spermatheca, and that GPB-1 and GPB-2, Gβ subunits, play a central role in regulating spermathecal contractility and Ca2+ signaling. This work identifies a signaling network in which Ca2+ and cAMP pathways work together to provide the correct coordinated contractions needed by the spermatheca for a successful ovulation.--Author's abstract