• Publikační typ
• abstrakty MeSH

GABAB receptors are G-protein coupled receptors for the inhibitory neurotransmitter GABA. Functional GABAB receptors are formed as heteromers of GABAB1 and GABAB2 subunits, which further associate with various regulatory and signaling proteins to provide receptor complexes with distinct pharmacological and physiological properties. GABAB receptors are widely distributed in nervous tissue, where they are involved in a number of processes and in turn are subject to a number of regulatory mechanisms. In this review, we summarize current knowledge of the cellular distribution and function of the receptors in the inner ear and auditory pathway of the mammalian brainstem and midbrain. The findings suggest that in these regions, GABAB receptors are involved in processes essential for proper auditory function, such as cochlear amplifier modulation, regulation of spontaneous activity, binaural and temporal information processing, and predictive coding. Since impaired GABAergic inhibition has been found to be associated with various forms of hearing loss, GABAB dysfunction could also play a role in some pathologies of the auditory system.

• MeSH
• buněčná membrána MeSH
• GABA MeSH
• hluchota * MeSH
• kognice MeSH
• receptory GABA-B * MeSH
• savci MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The cranial window technique has proven to be an effective method for in vivo imaging of cortical activity. However, given the invasive nature of this procedure, possible side effects could be expected in the nervous system. In this study, we evaluated the effects of unilateral cranial window surgery on auditory function in C57BL6 mice using electrophysiological and behavioral approaches. We found that one week after implantation, mice exhibited both increased thresholds and decreased amplitudes of their auditory brainstem responses. These changes were accompanied by a decrease in distortion product otoacoustic emissions, indicating a deterioration in cochlear function. In addition, behavioral testing of these mice revealed reduced suppression of their acoustic startle response by gap prepulse, suggesting a deficit in auditory processing or possibly the presence of tinnitus. The changes in auditory function appeared to be only partially reversible within four weeks after surgery. Thus, our findings suggest that cranial window implantation causes long-term functional changes in the auditory system that should be considered when interpreting data from optical imaging techniques.

• MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• protézy a implantáty MeSH
• sluch * MeSH
• sluchové kmenové evokované potenciály MeSH
• úleková reakce * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Noise-induced tinnitus is generally associated with hearing impairment caused by traumatic acoustic overexposure. Previous studies in laboratory animals and human subjects, however, have observed differences in tinnitus susceptibility, even among individuals with similar hearing loss. The mechanisms underlying increased sensitivity or, conversely, resistance to tinnitus are still incompletely understood. Here, we used behavioral tests and ABR audiometry to compare the sound-evoked responses of mice that differed in the presence of noise-induced tinnitus. The aim was to find a specific pre-exposure neurophysiological marker that would predict the development of tinnitus after acoustic trauma. Noise-exposed mice were screened for tinnitus-like behavior with the GPIAS paradigm and subsequently divided into tinnitus (+T) and non-tinnitus (-T) groups. Both groups showed hearing loss after exposure, manifested by elevated audiometric thresholds along with reduced amplitudes and prolonged latencies of ABR waves. Prior to exposure, except for a slightly increased slope of growth function for ABR amplitudes in +T mice, the two groups did not show significant audiometric differences. Behavioral measures, such as the magnitude of the acoustic startle response and its inhibition by gap pre-pulse, were also similar before exposure in both groups. However, +T mice showed significantly increased suppression of the acoustic startle response in the presence of background noise of moderate intensity. Thus, increased modulation of startle by background sounds may represent a behavioral correlate of susceptibility to noise-induced tinnitus, and its measurement may form the basis of a simple non-invasive method for predicting tinnitus development in laboratory rodents.

• Publikační typ
• časopisecké články MeSH

GABAB receptors (GBRs) are G protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GBRs regulate fast synaptic transmission by gating Ca2+ and K+ channels via the Gβγ subunits of the activated G protein. It has been demonstrated that auxiliary GBR subunits, the KCTD proteins, shorten onset and rise time and increase desensitization of receptor-induced K+ currents. KCTD proteins increase desensitization of K+ currents by scavenging Gβγ from the channel, yet the mechanism responsible for the rapid activation of K+ currents has remained elusive. In this study, we demonstrate that KCTD proteins preassemble Gβγ at GBRs. The preassembly obviates the need for diffusion-limited G protein recruitment to the receptor, thereby accelerating G protein activation and, as a result, K+ channel activation. Preassembly of Gβγ at the receptor relies on the interaction of KCTD proteins with a loop protruding from the seven-bladed propeller of Gβ subunits. The binding site is shared between Gβ1 and Gβ2, limiting the interaction of KCTD proteins to these particular Gβ isoforms. Substituting residues in the KCTD binding site of Gβ1 with those from Gβ3 hinders the preassembly of Gβγ with GBRs, delays onset and prolongs rise time of receptor-activated K+ currents. The KCTD-Gβ interface, therefore, represents a target for pharmacological modulation of channel gating by GBRs.

• MeSH
• draslíkové kanály metabolismus   genetika   MeSH
• gating iontového kanálu * fyziologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• proteiny vázající GTP - beta-podjednotky * metabolismus   genetika   MeSH
• proteiny vázající GTP - gama-podjednotky * metabolismus   genetika   MeSH
• receptory GABA-B * metabolismus   genetika   MeSH
• Xenopus laevis MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

GABA(B) receptors (GABA(B)Rs) regulate the excitability of most neurons in the central nervous system by modulating the activity of enzymes and ion channels. In the sustained presence of the neurotransmitter γ-aminobutyric acid, GABA(B)Rs exhibit a time-dependent decrease in the receptor response-a phenomenon referred to as homologous desensitization. Desensitization prevents excessive receptor influences on neuronal activity. Much work focused on the mechanisms of GABA(B)R desensitization that operate at the receptor and control receptor expression at the plasma membrane. Over the past few years, it became apparent that GABA(B)Rs additionally evolved mechanisms for faster desensitization. These mechanisms operate at the G protein rather than at the receptor and inhibit G protein signaling within seconds of agonist exposure. The mechanisms for fast desensitization are ideally suited to regulate receptor-activated ion channel responses, which influence neuronal activity on a faster timescale than effector enzymes. Here, we provide an update on the mechanisms for fast desensitization of GABA(B)R responses and discuss physiological and pathophysiological implications.

• MeSH
• buněčná membrána metabolismus   MeSH
• časové faktory MeSH
• GABA metabolismus   MeSH
• lidé MeSH
• neurony metabolismus   MeSH
• proteiny vázající GTP metabolismus   MeSH
• receptory GABA-B metabolismus   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The physiological functions of glycine receptors (GlyRs) depend on their subcellular locations. In axonal terminals of the central neurons, GlyRs trigger a slow facilitation of presynaptic transmitter release; however, their spatial relationship to the release sites is not known. In this study, we examined the distribution of GlyRs in the rat glutamatergic calyx of Held nerve terminal using high-resolution pre-embedding immunoelectron microscopy. We performed a quantitative analysis of GlyR-associated immunogold (IG) labeling in 3D reconstructed calyceal segments. A variable density of IG particles and their putative accumulations, inferred from the frequency distribution of inter-IG distances, indicated a non-uniform distribution of the receptors in the calyx. Subsequently, increased densities of IG particles were found in calyceal swellings, structures characterized by extensive exocytosis of glutamate. In swellings as well as in larger calyceal stalks, IG particles did not tend to accumulate near the glutamate releasing zones. On the other hand, GlyRs in swellings (but not in stalks) preferentially occupied membrane regions, unconnected to postsynaptic cells and presumably accessible by ambient glycine. Furthermore, the sites with increased GlyR concentrations were found in swellings tightly juxtaposed with GABA/glycinergic nerve endings. Thus, the results support the concept of an indirect mechanism underlying the modulatory effects of calyceal GlyRs, activated by glycine spillover. We also suggest the existence of an activity-dependent mechanism regulating the surface distribution of α homomeric GlyRs in axonal terminals of central neurons.

• MeSH
• GABA metabolismus   MeSH
• glycin metabolismus   MeSH
• krysa rodu rattus MeSH
• mozkový kmen cytologie   MeSH
• neparametrická statistika MeSH
• neurony cytologie   MeSH
• potkani Wistar MeSH
• presynaptická zakončení metabolismus   ultrastruktura   MeSH
• receptory glycinu metabolismus   ultrastruktura   MeSH
• synapse metabolismus   ultrastruktura   MeSH
• techniky in vitro MeSH
• vezikulární transportní protein 1 pro glutamát metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

GABAB receptors assemble from GABAB1 and GABAB2 subunits. GABAB2 additionally associates with auxiliary KCTD subunits (named after their K(+) channel tetramerization-domain). GABAB receptors couple to heterotrimeric G-proteins and activate inwardly-rectifying K(+) channels through the βγ subunits released from the G-protein. Receptor-activated K(+) currents desensitize in the sustained presence of agonist to avoid excessive effects on neuronal activity. Desensitization of K(+) currents integrates distinct mechanistic underpinnings. GABAB receptor activity reduces protein kinase-A activity, which reduces phosphorylation of serine-892 in GABAB2 and promotes receptor degradation. This form of desensitization operates on the time scale of several minutes to hours. A faster form of desensitization is induced by the auxiliary subunit KCTD12, which interferes with channel activation by binding to the G-protein βγ subunits. Here we show that the two mechanisms of desensitization influence each other. Serine-892 phosphorylation in heterologous cells rearranges KCTD12 at the receptor and slows KCTD12-induced desensitization. Likewise, protein kinase-A activation in hippocampal neurons slows fast desensitization of GABAB receptor-activated K(+) currents while protein kinase-A inhibition accelerates fast desensitization. Protein kinase-A fails to regulate fast desensitization in KCTD12 knock-out mice or knock-in mice with a serine-892 to alanine mutation, thus demonstrating that serine-892 phosphorylation regulates KCTD12-induced desensitization in vivo. Fast current desensitization is accelerated in hippocampal neurons carrying the serine-892 to alanine mutation, showing that tonic serine-892 phosphorylation normally limits KCTD12-induced desensitization. Tonic serine-892 phosphorylation is in turn promoted by assembly of receptors with KCTD12. This cross-regulation of serine-892 phosphorylation and KCTD12 activity sharpens the response during repeated receptor activation.

• MeSH
• alanin genetika   metabolismus   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• draslík metabolismus   MeSH
• fosforylace MeSH
• hipokampus cytologie   metabolismus   MeSH
• kultivované buňky MeSH
• metoda terčíkového zámku MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony metabolismus   MeSH
• proteinkinasy závislé na cyklickém AMP metabolismus   MeSH
• proteiny vázající GTP metabolismus   MeSH
• receptory GABA-B genetika   metabolismus   MeSH
• receptory GABA genetika   metabolismus   MeSH
• serin genetika   metabolismus   MeSH
• substituce aminokyselin MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The properties of glycine receptors (GlyRs) depend upon their subunit composition. While the prevalent adult forms of GlyRs are heteromers, previous reports suggested functional α homomeric receptors in mature nervous tissues. Here we show two functionally different GlyRs populations in the rat medial nucleus of trapezoid body (MNTB). Postsynaptic receptors formed α1/β-containing clusters on somatodendritic domains of MNTB principal neurons, colocalizing with glycinergic nerve endings to mediate fast, phasic IPSCs. In contrast, presynaptic receptors on glutamatergic calyx of Held terminals were composed of dispersed, homomeric α1 receptors. Interestingly, the parent cell bodies of the calyces of Held, the globular bushy cells of the cochlear nucleus, expressed somatodendritic receptors (α1/β heteromers) and showed similar clustering and pharmacological profile as GlyRs on MNTB principal cells. These results suggest that specific targeting of GlyR β-subunit produces segregation of GlyR subtypes involved in two different mechanisms of modulation of synaptic strength.

• MeSH
• dendritické trny fyziologie   MeSH
• elektrická stimulace MeSH
• elektrofyziologické jevy MeSH
• excitační postsynaptické potenciály účinky léků   MeSH
• glycin fyziologie   MeSH
• glycinové látky farmakologie   MeSH
• imunoelektronová mikroskopie MeSH
• imunohistochemie MeSH
• kinetika MeSH
• krysa rodu rattus MeSH
• metoda terčíkového zámku MeSH
• nervová zakončení metabolismus   MeSH
• potkani Wistar MeSH
• receptory glycinu účinky léků   metabolismus   MeSH
• receptory presynaptické metabolismus   MeSH
• sluchová dráha metabolismus   MeSH
• synapse metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Inhibitory circuits in the auditory brainstem undergo multiple postnatal changes that are both activity-dependent and activity-independent. We tested to see if the shift from GABA- to glycinergic transmission, which occurs in the rat medial nucleus of the trapezoid body (MNTB) around the onset of hearing, depends on sound-evoked neuronal activity. We prevented the activity by bilateral cochlear ablations in early postnatal rats and studied ionotropic GABA and glycine receptors in MNTB neurons after hearing onset. The removal of the cochlea decreased responses of GABAA and glycine receptors to exogenous agonists as well as the amplitudes of inhibitory postsynaptic currents. The reduction was accompanied by a decrease in the number of glycine receptor- or vesicular GABA transporter-immunopositive puncta. Furthermore, the ablations markedly affected the switch in presynaptic GABAA to glycine receptors. The increase in the expression of postsynaptic glycine receptors and the shift in inhibitory transmitters were not prevented. The results suggest that inhibitory transmission in the MNTB is subject to multiple developmental signals and support the idea that auditory experience plays a role in the maturation of the brainstem glycinergic circuits.

• MeSH
• ablace * MeSH
• agonisté receptorů GABA-A farmakologie   MeSH
• corpus trapezoideum fyziologie   MeSH
• inhibiční postsynaptické potenciály fyziologie   MeSH
• kochlea patofyziologie   chirurgie   MeSH
• krysa rodu rattus MeSH
• nervový přenos * MeSH
• nervový útlum účinky léků   fyziologie   MeSH
• novorozená zvířata MeSH
• receptory GABA-A fyziologie   MeSH
• receptory glycinu agonisté   metabolismus   fyziologie   MeSH
• sluchové kmenové evokované potenciály fyziologie   MeSH
• transportéry VIAAT metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH