**2. The evolution of calcium regulation in vertebrates**

In sea water the concentration of elemental calcium is approximately 10 mM. As a result, early eukaryotes living in a marine environment had easy access to calcium. Given this abundant supply of extracellular calcium, numerous intracellular processes evolved in simple eukaryotes that depended on this divalent cation. Such calcium-dependent processes were preserved in metazoans. Thus marine chordates and early vertebrate fish depended on calcium for cellular processes such as membrane permeability, neurotransmitter release, intracellular second messenger signaling, muscular contraction, neuromuscular excitability, and the actions of multiple calcium-dependent enzymes. Calcium's particular coordination chemistry facilitated many proteins' ability to reversibly bind divalent calcium ions, thus enabling signaling through such binding [3].

Calcium is much scarcer on land compared to the marine environment. As lobefinned fish, marine vertebrates believed to be the ancestors of the early amphibians, began to explore the periphery of the terrestrial environment, evolutionary pressure to develop a system of internal calcium balance mounted. A system of internal calcium homeostasis at the organismal level would ensure the continued preservation and function of numerous cellular and tissue operations that vitally depended on calcium.

Metabolically-active trabecular or cancellous bone in lobe-finned fish and associated hematopoietic bone marrow likely co-evolved [4]. These developments probably both lightened overall skeletal mass and provided a reliable internal source of calcium as a basis for calcium homeostasis. The lightening of skeletal mass was critical since lobe-finned fish and early amphibians had to come to terms with full gravitational force in their terrestrial movements, no longer buoyed by surrounding seawater in accordance with Archimedes' principle [5]. The potential significance of the close physical apposition of hematopoietic bone marrow to spongiform bone, inferred from X-ray synchrotron microtomography of fossilized lobe-finned fish humerus [4], is suggested by the realization that osteoclasts, cells uniquely specialized to mobilize ionized calcium via resorption of bone, develop from hematopoietic stem cell precursors [6]. In contrast, osteoblasts, which lay down osteoid and mineralize bone, derive from mesenchymal stem cells which are abundant in non-hematopoietic bone marrow.

Although analogs of Gcm2, Gata3, CaSR, PTH, and other genes associated with the development and function of human parathyroid glands are expressed in the fish gills, actual parathyroid glands are first seen in amphibians [7–9]. Complete surgical excision of parathyroid gland tissue in amphibians, reptiles, birds, and mammals results in tetany and death.
