**6. Insensitive target site**

Modifications of target sites as a result of point mutations on gene sequences have been also identified as mechanisms of resistance. Variations on genes encoding GABA receptors [31, 32], acetylcholinesterase [33], some detoxifying esterases [34, 35], and sodium channel gene sequences (22) have been discovered in different arthropods. The latter has been identified as *Kdr*-type resistance; this variation alters the molecular structure of the sodium channel, which is the target site of pyrethroid pesticides [36, 37].

*Kdr*-type resistance was firstly documented in *R*. *microplus* by He et al. [22]. It was shown that there is a variation in the sodium channel gene sequence at position 2134 where the base substitution of thymine by adenine (T2134A) results in an amino acid change from phenyla‐ lanine to isoleucine on the transmembrane segment 6 (S6), which is located on domain III of the para-type sodium channel gene [22].

Pyrethroid resistance in arthropods has been associated with nonsynonymous mutation on domains I, II, III, and IV of sodium channel genes [38, 39]. As already mentioned, two important variations have been previously identified in *R. microplus* sodium channel gene, a domain II variation (C190A) and the domain III variation (T2134A). The latter only found in ticks from Texas and Mexico [22, 40–42] and the former reported in Australia, Africa, and South America [23, 41, 42]. Although pyrethroid resistance in Mexican cattle tick populations has been mostly attributed to the domain III variation T2134A [22, 36, 39, 43], some authors have suggested that additional resistance mechanisms to the sodium channel variations must be present, since genotype frequencies from screened populations do not account for the level of phenotypic resistance observed in field [22, 39, 41].

Previous studies have documented the occurrence of variations on an esterase gene associated with pyrethroid resistance; however, this phenomenon seems to be linked to a pyrethroid metabolic detoxication mechanism since it has been consistently found in pyrethroid-resistant ticks [35, 37]. These results suggest that pyrethroid resistance in ticks is the result of genetic traits involved in both metabolic and insensitive target mechanisms, depending on which gene the variation occurs.
