3.5 billion to 700 million years ago


Higher animals have a number of complex systems in their bodies. These systems depend on specialized proteins which perform unique functions. Interestingly, many of the genes which produce these proteins belong to gene families whose origins date back to early prokaryotic and eukaryotic cells. Many of the most complex systems in higher animals owe their origins to the evolutionary events in their ancient unicellular ancestors.


The nervous system might have originated in primitive sensory cells which could stimulate local muscle contraction. The ancestral neurons might have been simpler neurosecretory cells which would develop the ability to conduct impulses later their evolution. Given that gut and pituitary hormones can be made in the brain and that neuropeptides can be made outside the nervous system, there is reason to believe that the nervous and endocrine systems are evolutionarily linked (LeRoith, 1981).
In the nervous and endocrine systems, a variety of signals must be sent between cells. A number of the signaling molecules found in the nervous and endocrine systems are known in organisms which lack these systems. Bacteria such as E. coli synthesize a protein similar to insulin and several protozoans are known to make peptides similar to adrenocorticotropic hormone, ß-endorphin, and dynorphin (LeRoith, 1981). Ciliates can possess receptors for substances which effect neurons such as ACh, neurepinephrine, and epinephrine. A mating pheromone in the protozoan Blepharisma resembles serotonin. The use of cAMP in signal transduction is involved in processes other than neural function and cAMP can even serve as an extracellular signal in slime molds (Mackie, 1990). Some plants use the signaling molecules glycine, GABA, glutamate, and ACh (Mackie, 1990). The simple nervous system of cnidarians includes the use of neuropeptides (Mackie, 1990).
In essence, the nervous system runs on electricity. Thought is electrical. Remembering your grandmother, preferring one outfit over another based on your favorite color, and recognizing the voice of your best friend all require that neurons conduct electricity. The ability of neurons to conduct electrical messages (action potentials) along their axons depends on their ability to generate resting electrical potentials across their cell membranes. This is a characteristic of most cells in the human body and many unicellular organisms as well. Some ciliates, such as Paramecium and Opalina, generate negative resting membrane potentials which, when stimulated, produce an influx of calcium which results in a reversal of the ciliary beat. Membrane depolarization results in the luminescent response in the dinoflagellate Noctiluca. Action potentials are known in the alga Nitella, the sensitive plant Mimosa and the venus flytrap (Prosser, 1973, p. 457). Yeast possess a number of genes which direct vesicle movement and CAM kinase II (which is essential for the formation of long term memory in vertebrates) (Mineta, 2003).
Although the ability to conduct electricity is most commonly identified with the nervous and muscular systems, other cell types can carry electrical messages as well. This more primitive transport of electrical messages may provide insight into the evolution of nervous tissue. The epithelia of ctenophores and jellyfish can conduct electrical messages without neurons. This neuroid conduction is known in epithelial and muscle sheets of higher animals as well (Hoar, 1983, p. 133-4). Electrical coupling is known to occur between the embryonic cells of squid, starfish, fish, and tadpoles. For example, in tadpole embryos, action potentials travel through the skin before nerves develop. Intercellular junctions (such as gap junctions) allow electrical coupling between cells in fly salivary glands, toad bladders, mouse livers, and malphigian tubes (Prosser, 1973, p. 461-2). Gap junctions allow electrical flow through cardiac and smooth muscle. Many neurons are linked by electrical synapses and these synapses are known between neurons in worms, mollusks, and arthropods and in vertebrates from fish through mammals. (Prosser, 1973, p. 483).

A neuron's ability to create resting and action potentials rests in its ability to transport ions, particularly potassium and sodium ions. Potassium channels are ancient proteins which evolved in organisms long before the ability to transmit electrical messages. Prokaryotes (eubacteria and archea) are known to possess potassium channels and these channels are homologous to those found in eukaryotes (Jiang, 2002). Eukaryotic channels retain their function when the eukaryotic channel pore is replaced by the pore from prokaryotic channels (Lu, 2001). As pictured below, the potassium channel is not only the simplest of the voltage regulated ion channels, its 6-transmembrane region structure (with the fourth unit being the voltage-regulated portion) is the prototype for the more complex sodium and calcium channels which are composed of four separate homologous regions. The simplest potassium channels form tetramers using four subunits of the same gene. (Darnell; Yellen, 2002).The potassium, sodium, and calcium voltage regulated channels are pictured below (after Darnell, p.782).

Neurons must be able to respond to a wide variety of neurotransmitters, neuropeptides, hormones, light, olfactory stimuli, taste stimuli, and other stimuli. Interestingly, most of these phenomena are perceived by the use of the members of one gene family, the G-protein coupled receptors. G-protein coupled receptors are used in many cell types other than those of the nervous system and evolved very early in the history of life, long before the evolution of animals. This superfamily of proteins share a set of 7 hydrophobic transmembrane regions connected by hydrophilic sections which form either intracellular or extracellular loops. This is a very old family found even in bacteria; bacteriorhodopsin is homologous to GPCRs of higher organisms although exon shuffling has changed the order of the transmembrane regions. Gene duplication had produced many of the subfamilies of the G proteins (Suga, 1999).

There are two major proteins responsible for the contraction of a muscle cell, actin and myosin. Myosin proteins possess a pivoting head which, after binding to ATP molecules for energy, can attach to specific sites on actin molecules, pivot, and return to their original position. Although these proteins are essential components of vertebrate muscle, they evolved in early cells are conserved throughout the groups of eukaryotes. Actin proteins are highly conserved proteins which constitute the majority of the eukaryotic cytoskeleton and can compose 10-20% of the total cellular protein of a non-muscle eukaryotic cell. These thin filaments are involved in organelle transport, cell motility, and cytokinesis (OMIM; Hoar, 1983).
The shape of all eukaryotic cells is determined by the shape of the protein cytoskeleton. These thin filaments are involved in organelle transport, cell motility, and cytokinesis. While yeast possess only one known actin gene, multiple genes are known from all protozoa, plants, and animals studied (Hightower, 1986). Although actin was formerly thought to be unique to eukaryotes, it is now evident that bacteria possess several homologs of actin, such as MreB and ParM, which can polymerize into filaments. There are 11 classes of myosin molecules in the myosin superfamily that are known from animals, plants, fungi, and protists. Some of the predominant myosins in amoeba are conserved in vertebrates. In addition to the conventional myosins found in vertebrate muscle, many are referred to as unconventional myosins which act as molecular motors which move along actin molecules. Seven of the known 11 classes of unconventional myosin molecules are found in vertebrates. (Mooseker, 1995).


The hormones of the endocrine system cannot affect the cells of the body unless the cells of the body have receptors which can perceive them. Many hormone receptors are G protein coupled receptors. This superfamily of proteins shares a set of 7 hydrophobic transmembrane regions connected by hydrophilic sections which form either intracellular or extracellular loops. This is a very old family found even in bacteria; bacteriorhodopsin is homologous to GPCRs of higher organisms although exon shuffling has changed the order of the transmembrane regions. Gene duplication had produced many of the subfamilies of the G proteins and protein tyrosine kinases before the lineages leading to modern sponges separated from those leading to higher animals (Suga, 1999). Unicellular yeast respond to mating pheromones through G-protein coupled receptors, reminiscent of homone-receptor interactions of animals (Blumer, 1988).


Hemoglobins are heme-containing proteins which reversibly bind oxygen. Hemoglobin is not unique to higher animals with circulatory systems: a variety of hemoglobins are known in bacteria, fungi, higher plants, most invertebrates and all vertebrates. All of them belong to the same globin gene family, having evolved from a single ancient ancestral protein. In bacteria and yeast, multi-domain proteins combine hemoglobin with other domains to produce proteins novel proteins such as flavohemoglobins. Bacterial flavohemoglobin can remove NO (nitric oxide) by reacting it with oxygen to form nitrate. When oxygen is not present, flavohemoglobin removes NO by promoting the conversion of N2O. Thus these molecules offer protection from NO in both aerobic and anaerobic conditions. In the ancient earth (and in the communities of deep sea vents), NO would have been far more abundant than oxygen.Carbonic anhydrase existed long before vertebrate circulatory systems, given that it is known from bacteria and plants (Hoar, 1983). The diverse carbonic anhydrase genes in living organisms, including the multiple genes which can be expressed in mammals, belong to one gene family (Tufts, 2003).


Bacteria and protists can release digestive enzymes into their environment and, after chemical digestion, absorb the simpler molecules.Serine proteases are a large family of enzymes in the human genome which function in diverse physiological processes ranging from digestion to coagulation (OMIM; Yosef, 2003). This is an ancient gene family which includes eubacterial digestive enzymes and the vertebrate digestive enzymes trypsin and chymotrypsin. (Hyman, 393).

The metabolic pathway that humans use to produce the urea excreted by the urinary system is called the arginine-urea pathway since it produces arginine for protein synthesis in addition to producing urea. It has other uses in the excretion of wastes since the production of ammonia can combat acidosis since ammonia can bind hydrogen ions and be excreted from the kidneys. Microorganisms use this pathway for the production of arginine only. Birds and insects lack this pathway and must include arginine in their diets. Thus the same metabolic pathway can be both nutritional and excretory. Some aspects of the arginine-urea metabolic pathway crucial for the human urinary system can be found in at least some members of all living groups, including bacteria, some reptiles, and insects. Some gastropods make use of a separate pathway to produce ammonia involving purine metabolism. In other organisms, from bacteria through humans, this second pathway serves only to synthesize purines as components of nucleotides. (Prosser, 1973).