Prestin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that is critical to sensitive hearing in mammals. It is encoded by the ''SLC26A5'' (solute carrier anion transporter family 26, member 5)

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Prestin is the

motor protein Motor proteins are a class of molecular motors that can move along the cytoskeleton of cells. They do this by converting chemical energy into mechanical work by the hydrolysis of ATP. Cellular functions Motor proteins are the driving force b ...

of the

outer hair cell Hair cells are the sensory receptors of both the auditory system and the vestibular system in the ears of all vertebrates, and in the lateral line organ of fishes. Through mechanotransduction, hair cells detect movement in their environment. ...

s of the inner ear of the

mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...

ian

cochlea The cochlea is the part of the inner ear involved in hearing. It is a spiral-shaped cavity in the bony labyrinth, in humans making 2.75 turns around its axis, the modiolus (cochlea), modiolus. A core component of the cochlea is the organ of Cort ...

. It is highly expressed in the outer hair cells, and is not expressed in the nonmotile inner hair cells. Immunolocalization shows prestin is expressed in the lateral

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

of the outer hair cells, the region wher
electromotility
occurs. The expression pattern correlates with the appearance of outer hair cell electromotility.

Function

Prestin is essential in auditory processing. It is specifically expressed in the lateral membrane of

s (OHCs) of the

. There is no significant difference between prestin density in high-frequency and low-frequency regions of the cochlea in fully developed mammals. There is good evidence that prestin has undergone adaptive evolution in mammals associated with acquisition of high frequency hearing in mammals. The prestin protein shows several parallel amino acid replacements in bats, whales, and dolphins that have independently evolved ultrasonic hearing and echolocation, and these represent rare cases of

convergent evolution Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last comm ...

at the sequence level. Prestin (mol. wt. 80 k Da) is a member of a distinct family of anion transporters, SLC26. Members of this family are structurally well conserved and can mediate the electroneutral exchange of

chloride The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...

and

carbonate A carbonate is a salt of carbonic acid, (), characterized by the presence of the carbonate ion, a polyatomic ion with the formula . The word "carbonate" may also refer to a carbonate ester, an organic compound containing the carbonate group ...

across the plasma membrane of mammalian cells, two

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conven ...

s found to be essential for outer hair cell motility. Unlike the classical, enzymatically driven motors, this new type of motor is based on direct voltage-to-displacement conversion and acts several orders of magnitude faster than other cellular motor proteins. A targeted gene disruption strategy of prestin showed a >100-fold (or 40 dB) loss of auditory sensitivity. Prestin is a transmembrane protein that mechanically contracts and elongates leading to electromotility of

s (OHC). Electromotility is the driving force behind the somatic motor of the cochlear amplifier, which is a mammalian evolution that increases sensitivity to incoming sound wave frequencies and, thus, amplifies the signal. Previous research has suggested that this modulation takes place via an extrinsic voltage-sensor (partial anion transporter model), whereby chloride binds to the intracellular side of prestin and enters a defunct transporter, causing prestin elongation. However, there is new evidence that prestin acts through an intrinsic voltage-sensor (IVS) in which intracellular chloride binds allosterically to prestin to modify shape.

Intrinsic voltage sensing

In this model of intrinsic voltage-sensing, the movement of ions generates a nonlinear capacitance (NLC). Based upon the generated voltage and the depolarized or hyperpolarized state of the cell, prestin will transition through two distinct steps, representing the three-state model of prestin modulation. Experiments show that with increasing depolarizing stimuli, prestin transitions from an elongated state to an intermediate state to a contracted state, increasing its NLC. Under hyperpolarizing conditions, NLC decreases and prestin transitions back to its elongated state. Of significance, increased membrane tension as characterized by prestin elongation decreases the chloride allosteric binding site affinity for chloride, perhaps playing a role in regulation of prestin modulation. The total estimated displacement of prestin upon modulation from elongated to contracted state is 3–4 nm². A recent study supports the IVS model showing that mutations of 12 residues that span the intracellular side of prestin's core membrane resulted in significant decrease in NLC. Eight of the 12 residues were positively charged and are hypothesized to make up the allosteric chloride binding site of prestin.

Anion transport

Although previously thought to be absent, anion transport has also been shown to be an important aspect of prestin's ability to drive electromotility of hair cells. This mechanism is independent of prestin's voltage-sensing capabilities based upon mutagenesis experiments showing that different mutations lead to effects in either anion-uptake or NLC, but not both. It is suggested that prestin contains an intrinsic anion-uptake mechanism based upon research showing concentration dependent sup>14Cormate uptake in Chinese hamster ovary (CHO) cells. These results could not be reproduced in oocytes. Therefore, prestin may require an associated cofactor for anion uptake in oocytes; however, this hypothesis is still under question. Experiments have shown that various anions can compete for prestin uptake including malate, chloride, and alkylsulfonic anions.

Discovery

Prestin was discovered by Peter Dallos's group in 2000 and named from the musical notation presto because of the speed of the protein. The prestin molecule was

patented A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...

by its discoverers in 2003.

Clinical significance

Mutations in the SLC26A5 gene have been associated with non-syndromic hearing loss.

Blockers

Electromotile function of mammalian prestin is blocked by the amphiphilic anion salicylate at millimolar concentrations. Application of salicylate blocks prestin function in a dose-dependent and readily reversible manner.