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The Taste and Smell Clinic

July 2003

The Role of Gustin (Carbonic Anhydrase VI) in Sensory Perception 

Professionals or patients who view this website may be unfamiliar with the concept that there is an intimate biochemical foundation which relates all sensory function, be it vision, hearing, touch, taste or smell. This short essay deals with this concept.

When life is considered, there are two fundamental characteristics assigned to it — the first nutrition, i.e., eating and growing, the second, reproduction. However, when the dark primeval ooze is considered and the world populated by single cellular organisms, there was an earlier life preserving function — i.e., the ability to sense pH. Thus, if single cell organisms were exposed to too acidic or basic an environment the organism would die before it had an opportunity to either eat or reproduce.

This fundamental mechanism of pH sensing was the first sense. The first “sense organ” was the enzyme gustin or carbonic anhydrase (CA) VI. This enzyme was located at the external membrane of all single cell organisms, on the leading edge of the cell, the edge that was exposed directly to the “new” external environment — if you would — the “nose” of the organism. It was the sensor which recognized the pH of the environment. It sent this sensory message about pH to an associated motor to which it was attached molecularly — a molecular motor — a muscle like protein such as myosin V. Upon command from the sensor the molecular motor, a muscle actin-like filament, moved the cell toward or away from the friendly or hostile external environment. The function of this molecular motor has recently been explored by Yildaz, et al in Science, 300:2061-2065. The function of the sensor, gustin or carbonic anhydrase VI, has been discussed by myself previously, in brief, in Drug Safety, 11:310-377, 1994.

This complex but critical system of sensory perceptive enzyme and molecular motor response is part of all life forms from the simplest to the most complex, including archaea, prokaryocytes and eukaryocytes. CA has been identified by histological techniques in the most primitive unicellular organisms and its function in pH identification defined. It as also been identified in sensory organs in complex, multicellular organisms reflecting a continuum of growth in functional complexity.

How does this system relate to taste and/or smell in humans? The first sense was smell. By that I mean the determination of pH was the first task of olfaction, the “nose”, the chemical sense which identified the acid-base environment. The first mechanistic manifestation of this sensory identification was through the first enzyme, CA.

CA is a zinc dependent enzyme. Thus zinc, which is the primary tissue trace metal upon which sensation depends, was initially utilized by single cell organisms, first for sensory perception and then, subsequently, in RNA and DNA polymerase, for processing of genetic activity and reproduction and for growth and development.

With this initial concept in mind it is possible to understand the next heirarchal set of complex tasks which allowed development of all sensory function with the primary anatomical and functional structure of sensory perception, be it vision, hearing, touch, taste or smell, dependent initially on CA and, in particular, on CA VI. Indeed, CAs been found in taste buds and in the olfactory epithelium of many animals and in sensory end organs of each sense, — in the eye, in the ear and in touch receptors in the skin of many animals.

The role of CA in these systems was enlarged, extended and made more complex subsequent to its initial role in pH perception. As the organism became more complex, with many more cells and more complex sensory demands to support, the sensory perceptive portion of the sense organ became anatomically detached from the leading edge of the cell and transferred to other portions of the organism, localized and focused in one or another end organ — the retina of the eye for vision, the organ of Corti for hearing, the taste bud perigemmal stem cells and receptor cells for taste, the globose basal stem cells and receptor cells of the olfactory epithelium for smell. The molecular motor aspect of the system was also modified since locomotion necessary to direct and propel the cell to a more friendly external environment was no longer needed. But the nexus of CA in sensory perception was conserved with the specific end-organ dependent on CA function for its growth and development. What was needed for continued sensory function was the continued use of CAs for growth and integrity of the sensory end organ which was now transferred to specialized sensory structures which performed specialized sensory perceptions. In this sense, the perceptive element was reformulated into a more complex functional element such that the enzymatic activity was now concerned with sensory organ anatomical growth and development along with its initial and superceded perceptive element.

Does pathology aid us in identifying these processes? Does pathology give us clues as to how these systems operate and to their history? Can this hypothesis be supported by clinical data? Yes. Pharmacological inhibition of CA impairs sensory perception. CA inhibitors given for a variety of clinical conditions inhibit various aspects of sensory perception. Thus, without CA function, sensory system function become impaired. Stopping drugs which are CA inhibitors usually restores sensory function.

Zinc deficiency also impairs sensory perception. Zinc deficiency induced by zinc lack in diet, by zinc chelation or by clinical disease processes which inhibit zinc absorption and/or utilization are associated with impairment of sensory perception including induction of taste and smell loss and distortion. Zinc itself has been useful in restoring sensory function in patients with zinc deficiency and with other causes of sensory dysfunction. This repair process using zinc has been helpful in improving macular degeneration in vision, in improving some viral induced hearing impairments with and without tinnitis and in improving taste and smell dysfunction.

As the organism grew more complex, multiple additional systems became involved with sensory system function. Functionality of CAs changed to accommodate growth and development of the sensory end organ. One focus of CA action was on the “sensory stem cell”. CA acted as a growth factor to initiate growth, development and sustained anatomical function of the sensory end organ. This action was conserved and the model for sensory end organ growth and development was duplicated and extended to all species. Thus, the original enzyme function of CA activity was preserved by its use as a growth factor to assist in growth, development and maintenance not only of taste buds and olfactory epithelia but also as a model for all sensory end organs. Its functionality was maintained through its action on stem cells of each sensory end organ. It was CA as a growth factor through its interactive program with the stem cell, in a manner similar to the action of nerve growth factor (NGF) on sympathetic ganglion cell differentiation, that the integrity of the elegant cellular repertoire of each sensory end organ was maintained, each sense organ differentiated within its own characteristic system but each ultimately dependent upon this Ur-growth factor as a resident supplier of direction and information for the generation of the cells of the end organ. Of course, as organismic complexity increased, other growth factors made their entrance onto the scene of sensory perception and complemented that of CA. The multiple other growth factors each played important individual and communal roles in sensory end organ growth and development — each one with timed expression and joint interactive functionality.

There are multiple examples to support this putative hypothesis. But for now, the important concept for readers of this web site is to recognize that there are fundamental principles underlying loss of taste and smell function which affect specific sensory end-organ function. Additionally, there are multiple fundamental principles underlying brain function and neural transmission along fiber tracts by which signals from the anatomically sound or pathologically impaired end organ are transmitted and processed by the brain either correctly or incorrectly. Failed or incorrect interactions among end organ, nerve and/or brain led to the symptoms which drew each of you to this website.

For you, as patients with dysfunction of taste and/or smell, recognition that these complex sensory systems in which you have impairments extend back to the beginning of time is important for you to understand. These impairments have fundamental physiological importance and a history which extends back into the distant past of phylogeny. It is mainly through appreciation of this history and complexity of these impairments that the work we are performing at The Taste and Smell Clinic of Washington, DC can be understood. They serve as the foundation we use in attempting to evaluate and correct the dysfunctions which you endure.

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