The OSNs form the most important aspect of olfactory detection in D. melanogaster. Their numbers exhibit great variations between the larval and adult stages of the fly. In larvae there are 21 OSNs per DO, whereas the adult fruit flies house much greater number of neurons. Each antenna displays ~1300 OSNs, whereas the actual number is 120 in each maxillary palp. An individual OSN typically embodies a single Or, although a few multiple receptor OSNs are also present in D. melanogaster [44,51]. The OSNs expressing identical receptor gene/genes then project to a specific glomerulus [52,53], where they synapse onto PNs and LNs [54] for further processing of the olfactory cues. A few studies have suggested that the number of OSNs converging into glomeruli varies between 52–53 OSNs per glomerulus [55]. However, each glomeruli has its own unique neuronal composition and glomerular volume, which is a result of varying numbers of OSNs and uniglomerular PNs received by different sets of glomeruli [56]. Additionally, an increased number of glomeruli per antennal lobe has been reported in D. melanogaster. The number is now 58, out of which 51 are olfactory [57] and 7, i.e., VP1d, VP1l, VP1m [58], VP2, VP3 [59], and VP4 [60,61,62] are thermo/hygrosensory in nature. They house a total of ~2600 antennal lobe sensory neurons (ALSNs) including OSNs and thermo/hygrosensory neurons (T/HSNs) [63].

The odorant receptors (Ors) in D. melanogaster are membrane-associated proteins by nature. They are encoded and expressed by Or genes [64,65]. The seven transmembrane domains possessed by these proteins are quite distinct and have no homology to the vertebrate GPCRs or Ors [66,67,68]. There are 60 Or genes in D. melanogaster, which encode 62 Ors by the process of alternative splicing (Table 1) [69,70,71]. However, studies using transgenic reporter techniques have changed the scenario to a considerable effect. These studies have revealed that the count of genes exclusive for antennal Ors is 40, whereas 7 genes translate receptors specific to maxillary palps [34,41,52]. The remaining Or genes are involved in the encoding of larval Ors and are not detectably expressed in adult fruit flies. There are 25 larval Ors, of which 13 are specifically expressed in larvae [70,72,73]. Additionally, Ors exhibit a unique feature. The receptors expressed in the antennae and maxillary palps of D. melanogaster are exclusive to them and are not expressed in each other, as established by several algorithmic studies. These studies have identified a dyad element that promotes the expression of maxillary-palp-specific Ors and a motif that represses their expression in the antennae [74]. One more restrictive feature of Ors is that the expression of Or genes in morphologically distinct sensilla follows a set pattern [75]. The study of this pattern has revealed a strong correlation between the developmental pathways of the sensilla and the types of Ors they express [32].

It is well-established that a solo Or gene is translated in each OSN [41,78,79]. However, a few studies have revealed interesting facts about Or gene expression. Each D. melanogaster OSN expressing an Or also expresses a co-receptor named as Orco/Or83b [65,80]. This co-receptor is essential to the appropriate ciliary routing and functioning of every single Or [65,81]. The flies devoid of Orco exhibit defective behavioral and electrophysiological responses to a number of odorants [67]. Besides this, four populations of OSNs co-express two conventional Ors (Or33a/Or56a, Or33b/Or47a, Or33b/Or85a and Or33c/Or85e) and a fifth one co-expresses one Or and one Gr (Or10a/Gr10a) along with the co-receptor Orco leading to a modulated ligand response profile [51,52]. A couple of recent works using cryo-electron microscopy have further given an insight into the functioning of Or/Orco heteromeric complexes. Butterwick et al., through structural analyses, has found that an Orco homomer consists of four subunits organized in a symmetrical fashion around a central pore. Each Orco subunit is further composed of seven transmembrane helical segments (S1–S7), out of which S7a (the cytoplasmic section) forms the crux of the anchor domain, whereas S7b (the transmembrane section) contours the central pore. The pore is narrowest at the extracellular end of S7b due to the presence of hydrophobic residues Leu473 and Val469. When a ligand binds to the Or/Orco heteromeric complex, the hydrophobic aperture is expanded. This central ion-conduction pathway then veers into the four lateral channels (6-Å long) that open to the cytosol, providing an uninterrupted pathway for the transfer of ions [82]. On a similar note, Marmol et al. has deciphered that the odorant receptor MhOr5 in Machilis hrabei exhibits identical quadrivial structural organization and functions similarly to Orco. Here, the binding of the ligand also dilates the S7b helices to gate the ion conduction pathway. In nutshell, these structural understandings of the Or and Orco have shed a light on the promiscuous nature of these receptors, allowing insects to have a versatile chemical recognition system [83].

Besides Ors, an additional group of receptors, called ionotropic receptors (Irs), is also involved in olfaction in D. melanogaster. Structural analyses have revealed their similarities to the ionotropic glutamate receptors (iGluRs) with a homology of less than 34% [84,85]. They also share the ion-channel-like characteristic of iGluRs, though the binding site for glutamate is not present [86,87]. The chemosensory apparatus of the larval stage is mainly distributed to the head region, encompassing the dorsal organ (DO), terminal organ (TO), ventral organ (VO), dorsal pharyngeal organ (DPO), dorsal pharyngeal sensilla (DPS), ventral pharyngeal sensilla (VPS), and posterior pharyngeal sensilla (PPS), all existing in pairs [45,88,89,90]. All of the above organs express Irs. A few Irs are also present in the body area that forms the complete larval repertoire together with the receptors of the head region (Table 2) [91]. Contrarily, the distribution of Irs in adult flies is quite diverse (Table 3). In the head region, they are dispersed in the antenna, labral sense organ (LSO), dorsal cibarial sense organ (DCSO), ventral cibarial sense organ (VCSO), and the labellum. The Irs are also expressed in the wings and legs of the fruit fly [91].

The Irs confer odorant responses much like the Ors, but more in-depth studies need to be conducted in this direction. The number of Ir genes in the D. melanogaster genome is 61, in addition to 2 putative pseudogenes. Among these, 17 genes encode the antennal Irs, while the rest of them are translated and scattered all over the fly’s body (both in the larval and adult stages); the latter are called divergent Irs. Amid the antenna, out of 13 Irs, the majority of them sense olfactory cues from amines, aldehydes and evaporative acids, and few Irs are hygrosensory or thermosensory in nature [60,85,91,92]. The remaining four Irs, i.e., Ir8a, Ir25a, Ir76b, and Ir93a are present and function as co-receptors in different amalgamations [93,94]. This paired functioning of Irs with co-receptors suggests that they work in tandem, resulting in ion channels responding to volatile odorant molecules [94,95]. Additionally, the identification of the co-receptor extra loop (CREL), a conserved sequence of the Ir co-receptor ligand-binding domain (LBD) has brought an array of new insights. It has helped in understanding the assembly and stoichiometry of Ir complexes and their intracellular transport in a much-improved way [96]. Besides olfaction, the Irs are also involved in the perception of gustatory stimuli. A group of approximately 35 Irs, the Ir20a clade is translated in all of the taste organs of the fly co-expressed with bitter or sweet Grs [97]. This is explained in detail later, in the gustatory section of the review.

Encoded by a clan of 52 genes, the Obps are found in abundance in D. melanogaster [92]. They are a group of highly divergent pint-sized proteins of 13–28 kDa secreted in the olfactory sensillar lymph [98,99]. The Obps ease the transportation of hydrophobic odorants such as a few food odorants, pheromones, etc. to the Ors [98,100,101]. The Obp76a, also known as LUSH, is essential for the detection of the pheromone cis-vaccenyl acetate (cVA) by Or67d in trichoid sensilla [102]. However, various studies have shown that even in the absence of Obp76a, D. melanogaster can detect cVA, refuting its essentiality [103,104]. Another study involving Obp28a, one of the most abundant Obps in fruit flies, showed that it was not involved in the transportation of odorants [105]. Contrary to these findings, recent work has established that Obp28a is essential for the detection of the floral odorant β-ionone by fruit flies [106]. Thus, these findings of the functioning of different Obps suggest that a much larger picture of the exact role and mechanism of their operation remains to be deciphered.