Tetrodotoxin as a Tool to Elucidate Sensory Transduction Mechanisms: The Case for the Arterial Chemoreceptors of the Carotid Body

Abstract

Carotid bodies (CBs) are secondary sensory receptors in which the sensing elements, chemoreceptor cells, are activated by decreases in arterial PO2 (hypoxic hypoxia). Upon activation, chemoreceptor cells (also known as Type I and glomus cells) increase their rate of release of neurotransmitters that drive the sensory activity in the carotid sinus nerve (CSN) which ends in the brain stem where reflex responses are coordinated. When challenged with hypoxic hypoxia, the physiopathologically most relevant stimulus to the CBs, they are activated and initiate ventilatory and cardiocirculatory reflexes. Reflex increase in minute volume ventilation promotes CO2 removal from alveoli and a decrease in alveolar PCO2 ensues. Reduced alveolar PCO2 makes possible alveolar and arterial PO2 to increase minimizing the intensity of hypoxia. The ventilatory effect, in conjunction the cardiocirculatory components of the CB chemoreflex, tend to maintain an adequate supply of oxygen to the tissues. The CB has been the focus of attention since the discovery of its nature as a sensory organ by de Castro (1928) and the discovery of its function as the origin of ventilatory reflexes by Heymans group (1930). A great deal of effort has been focused on the study of the mechanisms involved in O2 detection. This review is devoted to this topic, mechanisms of oxygen sensing. Starting from a summary of the main theories evolving through the years, we will emphasize the nature and significance of the findings obtained with veratridine and tetrodotoxin (TTX) in the genesis of current models of O2-sensing.

Recent progress in neuroactive marine natural products

“…Tahara improved the process of isolation and in 1910 named the puried molecule tetrodotoxin. 16 Not surprisingly, given the rich history associated with the investigation into TTX structure and pharmacological activities, there are an abundance of review articles focused on historical and more recent features of the molecule, 1,[17][18][19][20][21][22] its natural occurrence and biosynthesis, 3,23,24 potential ecological roles, [25][26][27] food safety, 28 analysis, 29,30 chemical synthesis, 23,31 pharmacology regarding interaction with voltage-gated sodium channels (VGSC), 1,3,11,[32][33][34][35][36] and its possible use clinically. 11 The guanidine toxins nonetheless continue to intrigue, yielding surprises and enticing potential for therapeutic application.…”

“…67 Using these small molecular probes, single Na V channel proteins were tracked in live neurons at a resolution beyond the diffraction limit of light microscopy using super-resolution imaging techniques, revealing channel localization and dynamics at an unprecedented scale. 67 Bifunctional, biotinylated forms of 4STX (33) and 11STX (34) were prepared from native STX. Those compounds exhibit comparable affinity to STX for binding to saxiphilin, an STXbinding protein, 68 and therefore also could be used to label neuronal VGSCs.…”

Hiperoxia perinatal e Hipoxia crónica como modelos experimentales para el estudio de la Transducción Hipóxica

“…En la sección anterior hemos detallado cómo el seguimiento de los movimientos del Ca 2+ a través de la membrana de las CQ llevó a la búsqueda de mecanismos que abrieran los canales de Ca 2+ dependientes de voltaje, que nuestro laboratorio había demostrado que la hipoxia activaba. En una revisión reciente (Rocher et al, 2011) se describe de forma precisa la historia del Ca 2+ como segundo mensajero en las CQ y su papel frente a los distintos estímulos.…”

Efectos inducidos por la hipoxia crónica intermitente en rata y cobaya como modelos animales de la apnea obstructiva del sueño

“…A la izquierda un corte de tejido con reacción inmunohistoquímica para TH mostrando en verde las células TH+. A la derecha, el mismo corte contrateñido con cresil violeta muestra la estructura general del tejido (Tomado ref 54. ).…”