Homeostatic control of body fluid CO 2 is essential in animals but is poorly understood. C. elegans relies on diffusion for gas exchange and avoids environments with elevated CO 2. We show that C. elegans temperature, O 2, and salt-sensing neurons are also CO 2 sensors mediating CO 2 avoidance. AFD thermosensors respond to increasing CO 2 by a fall and then rise in Ca 2+ and show a Ca 2+ spike when CO 2 decreases. BAG O 2 sensors and ASE salt sensors are both activated by CO 2 and remain tonically active while high CO 2 persists. CO 2-evoked Ca 2+ responses in AFD and BAG neurons require cGMP-gated ion channels. Atypical soluble guanylate cyclases mediating O 2 responses also contribute to BAG CO 2 responses. AFD and BAG neurons together stimulate turning when CO 2 rises and inhibit turning when CO 2 falls. Our results show that C. elegans senses CO 2 using functionally diverse sensory neurons acting homeostatically to minimize exposure to elevated CO 2.
► The major temperature, O 2, and salt-sensing neurons of C. elegans are CO 2 sensors ► AFD, BAG, and ASE neurons have unique CO 2-response properties ► O 2-sensing atypical soluble guanylate cyclases also mediate CO 2 neuronal responses ► CO 2 sensing involves both transient and persistent neuronal responses