Imelda McGonnell

Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders.

Conventional myosins – unconventional functions

While the discovery of unconventional myosins raised expectations that their actions were responsible for most aspects of actin-based cell motility, few anticipated the wide range of cellular functions that would remain the purview of conventional two-headed myosins. The three nonsarcomeric, cellular myosins—M2A, M2B and M2C—participate in diverse roles including, but not limited to: neuronal dynamics, axon guidance and synaptic transmission; endothelial cell migration; cell adhesion, polarity, fusion and cytokinesis; vesicle trafficking and viral egress. These three conventional myosins each take on specific, differing functional roles during development and maturity, characteristic of each cell lineage; exact roles depend on the developmental stage of the cell, cellular location, upstream regulatory controls, relative isoform expression, orientation and associated state of the actin cytoscaffolds in which these myosins operate. Here, we discuss the separate yet related roles that characterise the actions of M2A, M2B and M2C in various cell types and show that these conventional myosins are responsible for functions as unconventional as any performed by unconventional myosins.