Distinct Expression Patterns of Glycoprotein Hormone Subunits in the Lophotrochozoan Aplysia: Implications for the Evolution of Neuroendocrine Systems in Animals

Glycoprotein hormones (GPHs) comprise a group of signaling molecules critical for major metabolic and reproductive functions. In vertebrates they include chorionic gonadotropin, LH, FSH, and TSH. The active hormones are characterized by heterodimerization between acommon alpha and hormone-specific beta subunit, which activate leucine-rich repeat-containing G protein coupled receptors. To date, genes referred to as GPH alpha 2 and GPH beta 5 have been the only glycoprotein hormone subunits identified in invertebrates, suggesting that other GPH alpha and GPH beta subunits diversified during vertebrate evolution. Still the functions of GPH alpha 2 and GPH beta 5 remain largely unknown for both vertebrates and invertebrates. To further understand the evolution and putative function of these subunits, we cloned and analyzed phylogenetically two glycoprotein subunits, AcaGPH alpha and AcaGPH beta, from the sea hare Aplysia californica. Model based three-dimensional predictions of AcaGPH beta confirm the presence of a complete cysteine knot, two hairpin loops, and a long loop. As in the human GPH beta 5 subunit the seatbelt structure is absent in AcaGPH beta. We also found that AcaGPH alpha and AcaGPH beta subunits are expressed in larval stages of Aplysia, andwepresent a detailed expression map of the subunits in the adult central nervous system using in situ hybridizations. Both subunits are expressed in subpopulations of pleural and buccal mechanosensory neurons, suggesting a neuronal modulatory function of these subunits in Aplysia. Furthermore it supports the model of a relatively diffuse neuroendocrine-like system in molluscs, where specific primary sensory neurons release peptides extrasynaptically (paracrine secretion). This is in contrast to vertebrates and insects, in which releasing and stimulating factor from centralized sensory regions of the central nervous system ultimately regulate hormone release in peripheral glands. (Endocrinology 153: 5440-5451, 2012)