Sperm fusion with the egg initiates a signaling cascade that releases intracellular calcium (Cai2+) from the endoplasmic reticulum (ER). In sea urchins, Ca2+ is released as a single, large transient via two distinct pathways. The first depends on inositol 1,4,5-triphosphate (IP3) production and triggers the initial phase of Ca2+ release, while the second depends on nitric oxide (NO) production and is thought to maintain the duration of the Ca2+ wave. We identified a sea urchin homolog of the seven transmembrane G protein-coupled receptor for histamine (suH1R) on the egg cell surface that activates NO production. Treatment with histamine (HA) causes fluctuations in the resting levels of NO in the egg, while antagonists or antibodies of H1R inhibit the rise of NO normally observed at fertilization. Inhibition of SuH1R function decreases the maintenance, but not the amplitude, of the Ca2+ transient and suggests that it is an integral part of the overall pathway leading to egg activation at fertilization in sea urchins. © 2006 Wiley-Liss, Inc.