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Testosterone Estradiol Progesterone

Figure 10-1. The chemical structure of (A) adrenal and (B) gonadal steroid hormones.

Testosterone Estradiol Progesterone

Figure 10-1. The chemical structure of (A) adrenal and (B) gonadal steroid hormones.

functions. These would seem to be complex, but they can evolve relatively rapidly. Thus some insects have complete metamorphosis (holometabolism) whereas others have no larval or pupal stages. Similarly, in groups of sea urchins, tunicates, or amphibians, we find that within some branches of the phylogeny some species experience more and others less complex development (Raff 1996). Tadpoles are found in various branches of frogs, the stage apparently having evolved independently.

All insects make ecdysone, and ecdysone controls insect metamorphosis, but metamorphosis requires many physiological changes and thus many other proteins and functions. Genes for apoptosis, for example, genes for the synthesis of new cuticle, and genes for the hormones that control other stages of metamorphosis must have all coevolved, more or less tightly, yielding the array of stages of metamorphosis that we see today.

The signaling coordination responsible for these developmental traits may involve many genes and their responses but clearly is something easy and relatively simple to evolve. Some amphibians, such as the Mexican axolotl, do not undergo metamorphosis in the normal life course, but metamorphosis is inducible with exposure to thyroid hormone. Therefore, the axolotl is still genetically capable of losing its neotenous state, but this can only happen given the provocative physiological state. The key probably lies in the quantitative or qualitative control of a small number of critical developmental, signaling, hormonal, or growth factors.

Some invertebrate hormones have marked homology to vertebrate counterparts and thus are likely to have common ancestors, which these days is no surprise. However, homologous hormones do not necessarily perform homologous functions across species, just as homologous genes are not necessarily used in homologous pathways, and other hormones seem to be found only in invertebrates, suggesting that they arose after the vertebrate-invertebrate divergence.

Like the plant story described earlier, animal hormone function (e.g., reproductive cycling and behavior in vertebrates) may involve timed, quantitative differences among a series of hormones. Not surprisingly, in some instances at least the hormones are either functionally diverged members of a gene family, or modifications of a common base molecule (steroids). Once again, we see modular evolution by duplication with divergence leading to partial sequestration of related function.

Receptors

We introduced nuclear receptors in Chapter 7 (Table 7-3). They bind ligands that make their way directly into the cell, rather than intercepting them in the extracellular space. The first nuclear receptor is likely to have arisen some 1000-800mya, among the first metazoans. Nuclear receptors have not been found in plants. Virtually all vertebrates have the same six steroid receptors (estrogen receptors a and b, progesterone receptor, androgen receptor, glucocorticoid receptor, and mineralo-corticoid receptor). Three steroid receptors have been found in agnathostomes rather than six, including an estrogen receptor, a progesterone receptor, and a corticoid receptor but no androgen receptor (Thornton 2001; Thornton and Kelley 1998).

Despite the lack of structural homology between steroid hormones, thyroid hormone, and vitamin D3 molecules themselves, their nuclear receptors are homologous enough to be considered a steroid receptor superfamily. Nuclear receptors as a class are modular, consisting of four or five domains that function autonomously, and can be interchanged between related receptors without loss of function. This modularity presumably reflects a history of exon shuffling early in the evolution of the genes that code for these molecules (e.g., Patthy 1999).

Phylogenetic analysis of nuclear receptors led Laudet to propose six subfamilies of receptors, with members grouped by how they dimerize and bind DNA (Laudet 1997). Most of the six subfamilies are ancient and have receptors in both arthropods and vertebrates. The diversification of the superfamily may be the result of two waves of gene duplication (Escriva, Delaunay et al. 2000), which occurred before the divergence of lamprey and jawed vertebrates (Baker 1997; Thornton 2001; Thornton and Kelley 1998;Wallis 2000).There is no link between the ligand a receptor binds and the subfamily in which it is classed. That is, receptors that are closely related phylogenetically bind ligands with totally different biosynthetic pathways, suggesting that if nuclear receptors coevolved with their ligand, it was not a straightforward gain or loss of function during a gene duplication event, for example.

Phylogenetic analysis suggests that the ancestral steroid receptor was an estrogen receptor of some kind, with the androgen receptor emerging sometime after the vertebrate divergence. In lamprey, it is estrogen that regulates the development to sexual maturity in males as well as females, not androgen, suggesting that hormonal control over sexual dimorphism is relatively recent (Thornton 2001). A min-

eralocorticoid receptor has not been found in fishes or other lower vertebrates, indicating that it is the most recent of the steroid receptors. Agnaths apparently make most steroids, including testosterone, for which they have no receptor (personal communication, Thornton).

G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) were described in Chapter 7. As noted briefly in Table 7-4, there are several classes. The genes can be grouped into families in a number of different ways: by the molecular weight of their ligands, by the structure of their a-subunits, or by conserved amino acid structure. Five or six classes are conventionally agreed upon, and these include family I, the largest group of receptors, related to rhodopsin receptors; family II, including calcitonin-, PTH-, glucagon-receptors, and so forth; family III, containing metabotropic glutamate receptors and others, including a subgroup of vomeronasal receptors; family IV, comprised of STE2 yeast pheromone receptors; family V, yeast STE3 hormone receptors; and family VI, receptors related to slime mold cAMP receptors (Josefsson 1999). (These classes are sometimes designated by letter, A-F).

Phylogenetic analysis based on DNA sequence yields three large clades and several minor ones, all of which arose more than 800mya (Josefsson 1999; Wess 1998). In this analysis, families I, II, V, and VI plus some unclustered receptors form one large group, family III forms a smaller clade essentially as already classified, and family IV forms a final cluster. GPCRs in these families generally bind classes of ligands with similar functions, but with much diversity between the classes (Josefsson 1999). Receptors from these families were present in the acoelomate flat-worms of the Precambrian, showing that intercellular signaling is an ancient characteristic of multicellular organisms and probably of single-celled organisms.

Phenogenetic drift seems to have played a role in GPCR evolution. These genes comprise a large fraction of the genome (about three percent in mammals) and are used in a huge diversity of pathways. There is much structural diversity in the receptors as well as their ligands, even though they all operate similarly at the molecular level, so over evolutionary time there have been substitutions in the details but conservation of the mechanism and its basic logic.

GPCRs have been found in plants, but they do not seem to be as important in intercellular signaling in plants as they are in metazoans. A single gene for the a-subunit of the heterotrimeric G protein and one for the b-subunit are known in Arabidopsis, and homologous genes have been found in other plant species. In plants, calcium is the most important transducer of intracellular signals, as well as being involved in control of turgor pressure, cell growth, cell division, and other processes, with downstream effects including ion channel activation, gene expression, and vesicle fusion (Malho et al. 1998). It is also an important mediator of environmental and intercellular signals. How cells interpret calcium-transduced signal is still unclear, but calcium-binding proteins are involved. One set, the Calmodulin genes, bind to and regulate a wide variety of signaling proteins such as kinases, which phosphorylate transcription factors, cAMP phosphodiesterase, which degrades cAMP, as well as other enzymes, ion channels and pumps, various cytoskeletal components, and the like. Calmodulin is found in all eukaryotic cells. Each Calmodulin molecule binds four Ca2+ ions and changes conformation on binding, which allows the complex to bind to and activate molecules downstream.

Beyond its role in inducing conformational change in binding proteins, calcium action in a cell is dependent on spatiotemporal factors, such as the timing and location of transient membrane ion channels. Distribution of Ca2+ is not uniform throughout the cell but, on signaling, spikes at specific intracellular locations. At rest, cytosolic calcium concentration is maintained at between 10 and 100nM,but it can peak to between 1 and 5 |M. These transient spikes, or waves, are complex and not well understood, but it is known that the wave is initiated at a defined site by a defined signal or by passing through the plasma membrane at a single location. The wave is not transmitted by diffusion but by continuous release of calcium from sub-cellular stores, the ER, mitochondria, or other vesicles, followed by reuptake by cell compartments as the wave moves along. The wave can be constrained to specific locations in the cell by the factors involved in its production, and thus different parts of the cell can be separately regulated.

In Chapters 6 and 7 we described ion channels and the families of genes whose members complex to form these pores in cell membranes. These, too, have an evolutionary history. For example, there are 1 or 2 Na+ channel genes in invertebrates but 10 in mammals. Mammalian channel genes are found on four chromosomes, suggesting multiple duplications of an ancestral chromosome, which happened before divergence of teleosts and tetrapods. Sodium channel genes are linked to Hox gene clusters (Lopreato et al. 2001).

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