1. Gonadotropin-releasing hormone (GnRH) was originally isolated as a hypothalamic peptide hormone that regulates the reproductive system by stimulating the release of gonadotropins from the anterior pituitary. However, during evolution the peptide was subject to gene duplication and structural changes, and multiple molecular forms have evolved. 2. Eight variants of GnRH are known, and at least two different forms are expressed in species from all vertebrate classes: chicken GnRH II and a second, unique, GnRH isoform. 3. The peptide has been recruited during evolution for diverse regulatory functions: as a neurotransmitter in the central and sympathetic nervous systems, as a paracrine regulator in the gonads and placenta, and as an autocrine regulator in tumor cells. 4. Evidence suggests that in most species the early-evolved and highly conserved chicken GnRH II has a neurotransmitter function, while the second form, which varies across classes, has a physiologic role in regulating gonadotropin release. 5. We review here evolutionary aspects of the family of GnRH peptides and their receptors.

Gonadotropin-releasing hormone (GnRH) immunoreactive cells and fibers were revealed in olfactory regions, the ventral forebrain, and in the midbrain of the musk shrew (Suncus murinus). Immunoreactive neurons in olfactory and telencephalic areas were specific for the mammalian form of GnRH. Cell bodies in the midbrain, however, cross-reacted with an antibody specific for chicken-II GnRH. High-performance liquid chromatography and radioimmunoassay analyses confirmed these results; high levels of chicken II GnRH were present in the midbrain, and mammalian GnRH was detected in both fore-brain and midbrain. In addition, a third, late-eluting form of GnRH was revealed using high-performance liquid chromatography in both forebrain and midbrain of the musk shrew. Midbrain neurons containing GnRH have not been reported previously in a mammal, although mesencephalic GnRH immunoreactivity within cell bodies is common among nonmammalian vertebrates. Likewise, while multiple forms of GnRH have been reported in non-mammalian vertebrates and several metatherian species of mammals, this is the first report on multiple forms of GnRH in the brain of a placental mammal. Taken together, the findings suggest that this primitive eutherian mammal has retained the ability to produce GnRH protein in the midbrain. This feature of the GnRH system has been conserved among nonmammalian vertebrates, but appears to have been lost in modern placental mammal species. The functional significance of this group of neurons has yet to be determined.

Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy.