Ca2+ Sensor GCAP1: A Constitutive Element of the ONE-GC-Modulated Odorant Signal Transduction Pathway

The odorant signal is initiated at the ciliated apical border of the olfactory sensory neurons located in the main olfactory epithelium (MOE). Binding of an odorant to its receptor generates an electrical signal. The biochemical term for this process is odorant-transduction (reviewed in 1–4). It is a two-step process; in the first step, the signal generates its second messenger; in the second step, the second messenger transforms the signal into an electrical signal, which then becomes a means of signal transmission and the final perception of SMELL in the cortical layers of the brain. Till recently, the only second messenger of the odorant signal was considered to be cyclic AMP (5–9). Although, it still remains to be the major messenger, it is not the sole second messenger. In the incremental development of the field, it has now been established that cyclic GMP is also the second messenger of the odorant signal (10–14; reviewed in: 1, 15–17; also 18 for recent discussion). This signaling pathway resides in a small population of the olfactory receptor neurons (ORN) and is independent of the cyclic AMP signaling pathway (11, 12). The pathway begins with the ONE-GC membrane guanylate cyclase [also named GC-D (10)], which is co-present with the specific cyclic GMP-dependent components, cyclic GMP-specific cyclic nucleotide-gated channel subunit, CNGA3, and a cyclic GMP-dependent phosphodiesterase, PDE2 (11, 12). Importantly, the modi operandi of these two odorant pathways are radically different. In contrast to the cyclic AMP, cyclic GMP pathway does not function through the GTP-binding protein, Golf. It originates from ONE-GC, which is both the receptor for the odorants uroguanylin (19, 20) and green pepper (14, 21), and also the transducer through its guanylate cyclase activity. Thus, in line with the prototype ANF-RGC membrane guanylate cyclase signal transduction model (22), coexistence of the uroguanylin receptor and guanylate cyclase activities on a single transmembrane spanning polypeptide chain makes the cyclic GMP signal transduction pathway more direct and, theoretically faster. Among the multiple membrane guanylate cyclase signal transduction mechanisms, the odorant-linked ONE-GC mechanism is unique in several aspects (reviewed in: 17). It does not fit into the two traditional transduction models represented by the two membrane guanylate cyclase subfamilies. Unlike the Ca2+-modulated ROS-GC subfamily, it recognizes the signal through its extracellular domain. And, unlike the hormone receptor subfamily but like the ROS-GC subfamily, the odorant signal after its transmission to the intracellular domain undergoes multiple Ca2+-modulated steps. These steps amplify the signal prior to its final translation at the catalytic site into the production of cyclic GMP, the odorant’s second messenger. ONE-GC in addition to being an odorant receptor and transducer possesses an additional intriguing feature. Indirectly, through carbonic anhydrase enzyme, its catalytic site senses atmospheric CO2 and accelerates the production of cyclic GMP (23, 24). For these reasons, ONE-GC represents the third subfamily of membrane guanylate cyclases, which accounts for its hybrid features of the other two subfamilies: peptide hormone receptor and Ca2+-modulated ROS-GC (18, 20). In the current odorant, uroguanylin, two-step model, in step one, the odorant binds ONE-GC and primes it for stimulation, causing its partial activation. This step is Ca2+-independent (25). In step two, Ca2+-bound neurocalcin δ through a defined intracellular domain, saturates ONE-GC activity, and depolarizes the ciliary membranes (25). Besides neurocalcin δ, two other Ca2+-sensors co-exist with ONE-GC. They are hippocalcin (26) and GCAP1 (27). However, the applicability of the two-step model for these signal transducers has not been studied. This study investigates the role of GCAP1, at the biochemical and physiological level, in the odorant ONE-GC signal transduction. The findings demonstrate that it represents a new paradigm of signal transduction. This model is pictorially presented and it may become a prototype for certain other neurosensory processes.