Comparison Analysis Of The FKBP12.6Gene In Some Kinds Of Mammals

Heart failure occurs when the heart cannot pump sufficient blood through the body, and it is a very common condition. Sarcoplasmic reticulum (SR) is smooth endoplasmic reticulum found in muscle tissues, and reductions in its Ca2+content constitute a major pathogenic mechanism underlying dysfunctions that occur in heart failure. The cardiac ryanodine receptor type2(RyR2) is the major Ca2+release channel in the SR in cells that comprise cardiac muscle known as cardiomyocytes. During excitation-contraction (E-C), coupling intracellular Ca2+stored in the SR is released via RyR2to activate muscle contraction.In cardiac muscle cells, RyR2exists as a homotetrameric protein complex and interacts with an FK506binding protein (the12.6kDa FKBP12.6), protein kinase A (PKA) catalytic and regulatory subunits (RII), protein phosphatases1and2A (PP1and PP2A), and an anchoring protein, Makap. FKBP12.6are selectively associated with cardiac RyR2in situ to modulate the Ca2+-flux properties of the channel complex and stabilize the full conductance state during abnormal heart function, a prominent Ca2+leak occurs through the RyR2owning to a partial loss of FKBP12.6bound to RyR2, which is associated with a decreased rate of Ca2+release through the RyR2.Bats have evolved a number of extreme adaptations including flight, echolocation and hibernation. In order to adapt to their specialized lifestyles, the physiology of some bats organs have changed considerably in comparison with other mammals. One striking adaptation is extreme variation in heart rate. In some bats, heart rate can increase to more than1000beats per minute (bpm) during flight, decreasing to10bpm during hibernation. Moreover bats can begin flight relatively rapidly after arousing from torpor, so the changes in heart rate can be very rapid. This remarkable heart rate variation in hibernating bats prompted us to search a possible regulatory mechanism that induces this adaptation, since we hypothesized that the cardiac muscle E-C couplings of bats need more accurate and stable regulation.In this study we focus on FKBP12.6, sequencing the FKBP12.6coding region in the mouse, rat and10bat species, and comparing the sequences with those of11other mammal species retrieved from bioinformatics databases. We also analyze structural and potential functional changes in the FKBP12.6gene of a hibernating bat by using software simulation methods. We were especially interested to determine whether the amino acid sequences and structure of FKBP12.6in bats was specialized compared with other mammals given their extreme variation in heart rate associated with their abilities to hibernate and fly.We demonstrated the following:1. Based on alignments, the amino acid sequences in most mammals studied are very conserved. This phenomenon suggests that FKBP12.6plays a fundamental role in the functioning of the RyR2ion-channel, which is related to the heart rate regulation.2. There are twelve amino acids differences between FKBP12.6in Myotis ricketti and that of humans, which is completely different from the conservative FKBP12.6amino acid sequences of other animals. The large numbers of mutations in Myotis ricketti-FKBP12.6are probably associated with adaptive evolution, related to the large range of heart rates that reach extreme values during flight and hibernation.3. An additional helix exists in pocket ostium of Myotis ricketti-FKBP12.6, and the pocket cavity of Myotis ricketti-FKBP12.6is smaller than that of Homo sapiens-FKBP12.6for the existence of the frap β-sheet. This change leads to a more precise interaction between FKBP12.6and the RyR2ion-channel, which mediates a precise Ca2+-flux, may be necessary for the high heart rate of Myotis ricketti during flight.4. The theoretical isoelectric point (pI) of Myotis ricketti-FKBP12.6and Homo sapiens-FKBP12.6is6.09and8.62respectively, which suits different acid-base environments.5. The Instability index of Myotis ricketti-FKBP12.6and Homo sapiens-FKBP12.6is50.27and42.92respectively, which mediates a more highly reactivity of Myotis ricketti-FKBP12.6. Thus, the remarkable and accurate regulation of heart rate changes in bats such as hibernating Rickett’s big-footed bat (Myotis ricketti) may be related to novelty in the crystal structure and biochemical properties of FKBP12.6.