Mecanismos de Acoplamiento Estímulo-Respuesta
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BT_UMHMECANISMOS DE ACOPLAMIENTO
ESTIMULO-RESPUESTA
S = [ A·R ]·ε = [ RT ]·
[ A]
·ε = [ RT ]·ρ ·ε
Preamplificador
[ A] + K A
A+R AR Estímulo Efecto
S
R = Rmax ·
S + β'
Amplificador (eficiencia):
modulable por cofactores, enzimas, etc.
El preamplificador: densidad de receptores
k1
Activación de un receptor [A] + [R] [A·R]
k2
ocupación
velocidad de ocupación
redistribución de
estados
Unidad cuantal de estimulación
integració
n
Estimulación TOTAL [ A·R ] = [ RT ]· [ A]
[ A] + K A
Medidas bioquímicas de la densidad de receptores
Fijación de radioligandos + reserpina
Detectan SOLO la presencia de receptores
La respuesta está mediada también por el
acoplamiento estímulo-respuesta
Ejemplos de discrepancias
1. Corazón fetal de ratón (receptores β -
adrenérgicos sin respuesta)
2. Utero de conejo (los estrógenos afectan al
número de receptores α 2-adrenérgicos, pero
no a la respuesta)
nº receptores
3. El timo de ratón tiene 4.6 veces más receptores
β -adrenérgicos que el bazo, pero éste es 20
veces más sensible a los agonistas.
respuesta
4. Córtex de rata (los receptores muscarínicos
aumentan durante el desarrollo, pero su
respuesta disminuye)
5. Existencia de receptores no implicados en la
respuesta
El amplificador de potencia: relación estímulo-respuesta
Las respuestas tisulares son frecuentemente funciones NO LINEALES
de la ocupación de receptores.
Evidencias indirectas
Evidencias directas (Stephenson)
Alquilación (inactivación) de receptores
Respuesta
Ocupación
El amplificador de potencia: “receptores de reserva”
Muchos fármacos son más potentes de lo que es “necesario”
Receptor muscarínico Receptor α -adrenérgico
“Reservas” sobre los “receptores de reserva”
Ambigüedad del término “receptores de reserva”
Respuesta al
isoproterenol en
aurícula izquierda
de humanos en
varios estadios de
insuficiencia
cardíaca
Potencia de los mecanismos de acoplamiento estímulo-respuesta
La distinta sensibilidad a los fármacos en el mismo tejido, receptor y tipo de
respuesta se puede deber al número diferente de receptores (preamplificador)...
pero también a las distintas capacidades de amplificar las respuestas... Y éstas
dependen del número de elementos SATURABLES
Elementos saturables en el acoplamiento estímulo-respuesta
contracción
captación de calcio
ocupación
Vejiga urinaria de conejo
Elementos saturables en el acoplamiento estímulo-respuesta
Puntos estratégicos en la cascada E-R
frecuencia cardíaca
contracción
AMPc
Naturaleza de los mecanismos E-R: amplificación
fármaco + receptor F-R Estímulo Efecto
Mecanismos implicados en la amplificación
1. Cofactor o catalizador de un proceso celular
2. Disparador de otra cascada
3. Activación de una conductancia iónica o de
enzimas que producen un 2º mensajero
4. Sistemas con “memoria”
Acoplamiento selectivo y compartimentación intracelular
lipolisis
producción de AMPc
isoproterenol
BRL-37344
Aproximación matemática
RA ρ ocupación del receptor
=
RM ρ + β parámetro de ajuste:
componente tisular (procesos bioquímicos,
densidad de receptores)
componente del fármaco: eficacia intrínseca
RA S ε ·[ RT ]·[ A] β=
β'
= f (S ) = = f
RM S + β' [ A ] + K A
ε ·[ RT ]
RA
=
[ A·R ]
=
[ RT ]·ρ KE 1
RM [ A·R ] + K E [ RT ]·ρ + K E β= =
[ RT ] τ
Aproximación matemática
aurícula izq. rata
RA ε ·[ RT ]·[ A]
= f
RM [ A] + K A
β'
β=
ISO ε ·[ RT ]
aurícula izq. rata aurícula izq. cobaya
PREN
1 KE
β= =
τ [ RT ]
Ra
=
[ A]·τ
Rm [ A]·(τ + 1) + K A
extensor largo
cobaya
Common questions
Con tecnología de IAThe hypothesis of non-linear tissue responses to receptor occupation is supported by examples such as fetal mouse heart β-adrenergic receptors showing no response and the variability in response within the rat cortex despite an increase in muscarinic receptors. This non-linearity suggests that downstream signaling mechanisms and receptor reserve influence response independently of receptor occupancy. For drug design, this emphasizes the need for targeting downstream signaling pathways and understanding tissue-specific coupling mechanisms to effectively modulate physiological responses .
Receptors of reserve, or 'spare receptors,' refer to the excess receptors that exist beyond those needed to elicit a maximal response upon drug binding. They amplify the stimulus-response relationship by allowing a full response even if only a fraction of receptors are occupied, thereby enhancing the perceived potency of drugs. This concept explains why certain tissues exhibit non-linear responses to receptor occupancy, as evidenced in cases such as the isoproterenol response in human atria at different stages of heart failure, where changes in sensitivity may be observed despite receptor number .
Signal amplification contributes to tissue-specific variability in drug response by enhancing or suppressing signals at varying stages of the response cascade. This involves different saturable elements, such as enzyme activation or secondary messenger production, which can vary between tissues. In the rabbit urinary bladder, for instance, factors like calcium uptake during contraction illustrate how amplification processes can lead to varied drug efficacies and response profiles, even when the external stimulus remains constant .
'Saturable elements' are crucial in the stimulus-response coupling mechanism as they define thresholds for maximal response and the extent to which a response can be modulated. They include active sites or cellular components that reach a maximum capacity, such as receptor binding sites or secondary messenger systems. Their saturation determines the non-linear escalation of responses, influencing dose-response relationships and the therapeutic window of drugs .
Variations in tissue sensitivity despite similar receptor numbers may stem from differences in stimulus-response coupling mechanisms such as receptor reserve, cofactor presence, and downstream signaling pathways. For example, despite having 4.6 times more β-adrenergic receptors than the spleen, the mouse thymus is 20 times more sensitive to agonists, illustrating that factors beyond receptor density, like intracellular signaling diversity and amplifying mechanisms, play critical roles in modulating response .
Mathematical models provide insights into the interaction between drug efficacy and receptor occupation by allowing quantification and simulation of complex biochemical interactions. These models incorporate parameters like receptor density, efficacy, and occupancy to predict outcomes of drug-receptor interactions. For instance, models used in left atria of rats and guinea pigs account for variables such as receptor reserve and tissue sensitivity, helping to elucidate how a drug's intrinsic efficacy translates into biological effects .
Enzymes and coenzymes play pivotal roles in signal amplification by either facilitating or hindering catalytic processes essential for cascade propagation. Enzymes such as kinases or phosphatases modulate the activity of downstream effectors through phosphorylation, while cofactors might increase or decrease enzyme efficacy by altering activation energy or conformation states. This orchestration of enzymatic activity is integral in ensuring appropriate cellular responses to stimuli, as reflected in biochemical signatures like AMPc in cardiac tissues .
Discrepancies in receptor-response highlight complexities in stimulus-response coupling, as seen in several biological systems. For example, rabbit uterine estrogen affects α2-adrenergic receptor numbers without changing response, and mouse cortex muscarinic receptors increase but response decreases. These discrepancies suggest that factors beyond mere receptor density affect response, such as signal amplification and cellular context, challenging the assumption that receptor density directly correlates with the magnitude of a physiological response .
The efficiency of the stimulus-response mechanism is modulated by factors such as coenzymes and receptor density through enhancement and gatekeeping of signal transmission. Coenzymes act as either facilitators or inhibitors, influencing the preamplification and amplification phases by altering energy and signaling environments. Receptor density, often assessed through radioligand binding, affects signal reception capacity and interacts with non-linear tissue responses that vary with receptor saturation. This modulation leads to variable biological reactions depending on the interplay of these factors .
Stimulus-response coupling is critical because it elucidates how signals from occupied receptors are translated into cellular responses, which can vary widely across tissue types due to differences in receptor types, densities, and intracellular signaling pathways. This concept helps discern why tissues such as the rabbit uterus and mouse thymus have distinct responses to similar stimuli, guiding pharmacological strategies to tailor drug therapies to specific physiological contexts by targeting appropriate coupling mechanisms .