PHARMACODYNAMICS by MikeJenny

VIEWS: 8 PAGES: 45

									  PHARMACODYNAMICS

     YORAM ORON, PhD
PROFESSOR OF PHARMACOLOGY
   Sackler Faculty of Medicine
       Tel Aviv University
ABOUT DRUGS
DRUG – ANY CHEMICAL COMPOUND USED
         TO TREAT A DISEASE
  AND/OR POISON A LIVING ORGANISM

              PRINCIPLES
1. MANY DRUGS HAVE THERAPEUTIC
   EFFECTS
2. ALL DRUGS HAVE SIDE EFFECTS
3. UNLIKE IN HOMEOPATHY, BOTH
   EFFECTS ARE DOSE-DEPENDENT
      ALL DRUGS HAVE
   THERAPEUTIC WINDOW
BELOW MIN CONCENTRATION –
  INSUFFUCIENT EFFICACY
ABOVE MAX CONCENTRATION-
UNACCEPTABLE SIDE EFFECTS
 FOR A SPECIFIC PATHOLOGY

 RATIO MAX/MIN CONCENTRATION
  A MEASURE OF DRUG SAFETY
 THERAPEUTIC INDEX-TI



A STANDARD MEASURE OF DRUG
     SAFETY = LD50/EC50
  MORE SENSITIVE MEASURES,
   SUCH AS SE5/EC50 MAY BE
           BETTER
DRUG TARGETS
         DRUG TARGETS

• MINORITY – BASED ON COLLIGATIVE
  PROPERTIES, E.G. pH OR OSMOTIC
  PRESSURE
• MAJORITY – COVALENT OR NON-
  COVALENT BINDING TO RECEPTOR
  MOLECULES =RECEPTORS
• RECEPTORS ARE DIVIDED INTO
  PHARMACOLOGICAL AND
  PHYSIOLOGICAL
           RECEPTORS
• PHYSIOLOGICAL RECEPTORS BIND
  NATURAL AGONISTS THAT HAVE
  BIOLOGICAL INFORMATION CONTENT
  (HORMONES, NEUROTRANSMITTERS,
  AUTACOIDS, ETC.)
• HENCE, PHYSIOLOGICAL RECEPTORS
  CAN BE PHARMACOLOGICALLY
  STIMULATED BY AGONIST DRUGS OR
  INHIBITED BY ANTAGONIST DRUGS
• DRUGS AFFECTING PHYSIOLOGICAL
  RECEPTORS EVOKE CONCERTED
  PHYSIOLOGICAL RESPONSES
  EMBEDDED IN THE NATURAL FUNCTION
  OF THE RECEPTOR
             RECEPTORS

• PHARMACOLOGICAL RECEPTORS BIND
  SYNTHETIC ANTAGONISTS THAT HAVE NO
  BIOLOGICAL INFORMATION CONTENT
• HENCE, PHARMACOLOGICAL RECEPTORS CAN
  BE MAINLY INHIBITED PHARMACOLOGICALLY
  BY ANTAGONIST DRUGS
• DRUGS AFFECTING PHARMACOLOGICAL
  RECEPTORS MAY DISRUPT CONCERTED
  PHYSIOLOGICAL RESPONSES EMBEDDED IN
  THE NATURAL FUNCTION OF THE RECEPTOR
               EXAMPLES
• ACETYLCHOLINE BINDS TO NICOTINIC OR
  MUSCARINIC RECEPTORS, TO INDUCE SKELETAL
  MUSCLE CONTRACTION FOLLOWED BY
  DESENSITIZATION OR STIMULATE SMOOTH
  MUSCLE CONTRACTION (E.G. ILEUM)
• TUBOCURARINE OR ATROPINE BIND TO NICOTINIC
  OR MUSCARINIC RECEPTORS, TO BLOCK
  SKELETAL MUSCLE OR SMOOTH MUSCLE
  CONTRACTION
• ESTERASE INHIBITORS (E.G. NEOSTYGMINE) BIND
  TO ACETYLCHOLINE ESTERASE AND INDUCE
  SKELETAL MUSCLE CONTRACTION FOLLOWED BY
  DESENSITIZATION OR STIMULATE SMOOTH
  MUSCLE CONTRACTION (E.G. ILEUM)
               EXAMPLES
• NOREPINEPHRINE (NE) BINDS TO ALPHA-1 OR
  BETA-2 ADRENERGIC RECEPTORS ON BLOOD
  VESSELS, TO INDUCE CONTRACTION (BP
  ELEVATION) OR STIMULATE SMOOTH MUSCLE
  RELAXATION (BP DECREASE)
• PRAZOSIN OR PROPRANOLOL BIND TO ALPHA-1 OR
  BETA-2 ADRENERGIC RECEPTORS , TO BLOCK
  VASCULAR SMOOTH MUSCLE CONTRACTION OR
  RELAXATION
• UPTAKE INHIBITORS (E.G. COCAIN) BIND TO
  UPTAKE-1TRANSPORTER AND BLOCK NE
  REMOVAL, TO ENHANCE VASCULAR MUSCLE
  CONTRACTION
      DRUGS ACTING ON
  PHYSIOLOGICAL RECEPTORS


• AGONISTS: RESULT IN RECEPTOR
  ACTIVATION – DIVIDED INTO FULL AND
  PARTIAL
• ANTAGONISTS: PREVENT RECEPTOR
  ACTIVATION BY NATURAL AGONISTS -
  DIVIDED INTO COMPETITIVE SIMPLE
  (NEUTRAL), INVERSE AND NON-
  COMPETITIVE
      DRUGS ACTING ON
  PHYSIOLOGICAL RECEPTORS


• PARTIAL AGONISTS: EXHIBIT EFFICACY
  OF LESS THAN 1.0.
• ALL PARTIAL AGONISTS ARE PARTIAL
  COMPETITIVE ANTAGONISTS
• INVERSE AGONISTS: ACT AS SIMPLE
  NEUTRAL ANTAGONISTS, EXCEPT IN
  TISSUES EXPRESSING CONSTITUTIVELY
  SIGNALING RECEPTORS (SEE BELOW)
RECEPTOR ACTIVATION
  MECHANISM OF ACTIVATION OF
   PHYSIOLOGICAL RECEPTORS


• RECEPTORS EXIST NATURALLY IN TWO
  THERMODYNAMIC STATES IN RAPID
  EQUILIBRIUM: INACTIVE – Ri AND ACTIVE –
  Ra. USUALLY, THE INACTIVE STATE IS
  PREDOMINANT


          Ri                 Ra
  MECHANISM OF ACTIVATION OF
   PHYSIOLOGICAL RECEPTORS



• AGONISTS BIND TO Ra, STABILIZING THE
  ACTIVE STATE. THIS RESULTS IN SHIFTING
  OF MOST OF THE RECEPTORS TO AN
  AGONIST-Ra STATE
Ri               Ra+AG            AG*Ra
MECHANISM OF INACTIVATION OF
 PHYSIOLOGICAL RECEPTORS


• SIMPLE COMPETITIVE ANTAGONISTS BIND
  TO BOTH FORMS OF THE RECEPTOR,
  WITHOUT AFFECTING THE EQUILIBRIUM,
  PREVENTING SHIFT TO THE ACTIVE
  CONFORMATION


 ANT*Ri       Ri     Ra      ANT*Ra
MECHANISM OF INACTIVATION OF
 PHYSIOLOGICAL RECEPTORS
            TERNARY COMPLEX MODEL IS
            THE SIMPLEST ONE TO
      L’    EXPLAIN NEUTRAL AND
            INVERSE AGONISTS.
            FOR NEUTRAL ANTAGONISTS,
            THE EQUILIBRIUM CONST.
                       L’ = L

           NOTE: A DENOTES LIGAND
            K, K’ –EQUIL. CONST. BETWEEN
             INACTIVE AND ACTIVE
             RECEPTOR FORMS
MECHANISM OF INVERSE
     AGONISTS

       FOR INVERSE AGONISTS,
       THE EQUILIBRIUM CONST.
  L’
               L’  L

         THEY ESTABLISH AN
        EQUILIBRIUM, IN WHICH
       THE % OF ACTIVE FORM IS
          HIGHER THAN W/O
         AGONIST, BUT LOWER
             THAN 100%
DOSE RESPONSE
                                     DOSE RESPONSE CURVE
                               Dose response (EC50 1 nM)                  FOLLOWS THE
              100
                   90
                                                                            CLASSICAL
                   80
                                                                           ADSORPTION
 of maximal response




                   70
                   60
                                                                          ISOTHERM OF
                   50
                   40                           L’
                   30                                                       LANGMUIR
                   20
 %




                   10
                       0
                           0       20      40      60       80   100
                                        Agonist Conc (nM)
                                                                            = C/(C+K)

POTENCY – EC50 OR ED50                                                  = RELATIVE EFFECT
EFFICACY – RELATIVE                                                    C = [AGONIST]
MAX EFFECT
                                                                       K = EC50 OR ED50
            DOSE RESPONSE                                                                 REPRESENTATIONS

                                                                                                                            Dose response (EC50 1 nM)
            Double-Inverse dose response
                                                                                                                                       100
      0.22
                                                                                                                                        90
       0.2
                                                                                                                                        80




                                                                                            of maximal response
      0.18
                                                                                                                                         70
      0.16
                                                                                                                                         60
      0.14
 response




      0.12                                                                                                                               50
       0.1                                                                                                                               40
                                                                                                                                         30
1/%




      0.08
      0.06                                                                                                                               20




                                                                                            %
      0.04                                                                                                                               10
      0.02                                                                                                                                0
         0                                                                                               0.01                 0.1             1         10        100
      -2 0     2   4   6   8   10   12       14 16   18    20                                                                       Agonist Conc (nM)
                           1/[ag]
                                                     Inverse dose response
                                                                                                                          Eadie-Hoffstee or Scatchard type
                                                            0.04
                                                                                                         100

                                                            0.03
                                                                                                              75
                                        response




                                                            0.02




                                                                                            max response
                                                                                                              50
                                     1/5%




                                                            0.01
                                                                                                              25




                                                                                                                               AG
                                                                                            %




                                                                                                                               /[
                                                                                                                               ]
                                                                 0
                                              -1.5        -0.5        0.5     1.5   2.5                           0
                                                                                                                      0       20         40       60         80   100
                                                                     1/[ag]
                                                                                                                                     % of max response
DOSE RESPONSE                                                               COMPETITIVE INHIBITION
                             Dose response (EC50 1 nM) or                                            Inverse dose response
                              +Ant([Ant]=0.5nM, Ki=0.1 nM)
                                                                                     0.22
                                                                                      0.2
                       100                                                           0.18
                        90                                                           0.16
                        80                                                           0.14




                                                                                response
       of maximal response




                        70                                                           0.12
                        60                                                            0.1




                                                                             1/5%
                        50
                                                                                     0.08
                        40
                                                                                     0.06
                        30
                                                                                     0.04
                        20
       %




                                                                                     0.02
                        10
                                                                                        0
                         0
                                                                                     -2 0            2   4    6   8    10 12 14 16 18 20
                             0      20       40       60         80   100
                                          Agonist Conc (nM)                                                       1/[ag]



                             Dose response (EC50 1 nM) or                                    Eadie-Hoffstee or Scatchard type
                              +Ant([Ant]=0.5nM, Ki=0.1 nM)
                                                                                       100
                                           100
                                            90
                                                                                           75
                                            80
 of maximal response




                                            70

                                                                              max response
                                            60
                                                                                           50
                                            50
                                            40
                                            30                                             25


                                                                                                         AG
                                                                              %




                                            20

                                                                                                         /[

                                                                                                         ]
 %




                                            10
                                             0                                               0
              0.01                0.1             1         10        100                        0       20       40       60     80   100
                                        Agonist Conc (nM)                                                     % of max response
DOSE RESPONSE
                       Dose response (EC50 1 nM) or
                                                                       NON-COMPETITIVE INHIBITION
                        +Ant([Ant]=0.2nM, Ki=0.1 nM)
                                                                                                    Inverse dose response
              100
               90                                                                   0.1
               80
 of maximal response




               70                                                                0.08
               60
               50
                                                                                 0.06




                                                                            response
               40
               30
                                                                                 0.04




                                                                           1/%
               20
 %




               10
                0                                                                0.02
                       0     20        40       60          80   100
                                    Agonist Conc (nM)                                   0
                                                                                  -2            0   2   4    6   8    10 12 14 16 18 20
                                                                                                                 1/[ag]
                       Dose response (EC50 1 nM) or
                        +Ant([Ant]=0.2nM, Ki=0.1 nM)
                                                                                            Eadie-Hoffstee or Scatchard type
                                      100
                                                                                       100
                                       90
                                       80
 of maximal response




                                       70                                               75
                                       60
                                       50                                    max response
                                       40                                               50
                                       30
                                       20
 %




                                                                                        25

                                                                                                        AG
                                                                             %




                                       10
                                                                                                        /[

                                                                                                        ]
                                        0
              0.01           0.1            1          10        100                        0
                                   Agonist Conc (nM)                                            0       20       40       60     80   100
                                                                                                             % of max response
LIGAND-RECEPTOR BINDING
                               LIGAND-RECEPTOR BINDING
                                                                       FOLLOWS THE
                              Ligand Binding (Kd 1 nM)
                                                                         CLASSICAL
             100
                                                                        ADSORPTION
 of maximal binding




                  80
                  60
                                                                       ISOTHERM OF
                  40                           L’
                  20                                                     LANGMUIR
 %




                      0


                                                                         = L/(L+K)
                          0       20      40     60       80   100
                                       Ligand Conc (nM)




                                                                       = RELATIVE
AFFINITY – KD                                                        BINDING (B/BMAX)
RECEPTOR DENSITY                                                     C = [FREE LIGAND]
                                                                          K = KD
                      LIGAND-RECEPTOR BINDING
       100
                                                              USUALLY
                                                          REPRESENTED AS
          75
                                                          SCATCHARD PLOT
max binding




          50

                                   L’                    NON-LINEAR PLOT
          25
                                                          SUGGESTS MORE
%




                      C
                      /[
                      ]




              0
                  0   20      40      60      80   100
                                                           THAN A SINGLE
                           % of max binding
                                                             RECEPTOR
AFFINITY (KD) -SLOPE                                        POPULATION
RECEPTOR DENSITY, HERE SHOWN
AS % OF MAX, BUT USUALLY AS
REAL VALUE (E.G. pmol/mg prot or #
of receptors/cell)
SPARE RECEPTORS
         SPARE RECEPTORS
SPARE RECEPTORS or RECEPTOR RESERVE A
SITUATION WHERE THERE ARE MORE RECEPTORS
THAN NECESSARY FOR MAXIMAL PHYSIOLOGICAL
RESPONSE.
THE BINDING ISOTHERM - B/Bmax=L/(L+Kd),
DESCRIBES THE PROPORTION OF RECEPTORS
OCCUPIED AT A GIVEN LIGAND CONCENTRATION L.
ONLY WHEN B/Bmax IS MULTIPLIED BY A REAL
CELLULAR RECEPTOR NUMBER WE GET THE
NUMBER OF OCCUPIED RECEPTORS. IF THIS
NUMBER IS MORE THAN THE NUMBER REQUIRED
FOR FULL RESPONSE, NO FURTHER RESPONSE IS
OBSERVED, ALTHOUGH MORE AND MORE
RECEPTORS ARE OCCUPIED AT HIGHER AND
HIGHER L.
DOSE RESPONSE
   & SPARE
             REPRESENTATIONS OF
  RECEPTORS DOSE-RESPONSE WITH A
                                                                          1000-FOLD RECEPTOR RESERVE
                                                                          COMPARED TO NO RESERVE

                                Dose response (kd 1 nM)                                           Dose response (kd 1 nM)

               100                                                                                                 100
                    90                                                                                              90
                    80                                                                                              80
  of maximal response




                                                                            of maximal response
                    70                                                                                              70
                    60                                                                                              60
                    50                                                                                              50
                    40                                                                                              40
                    30                                                                                              30
                    20
  %




                                                                            %



                                                                                                                    20
                    10                                                                                              10
                        0                                                                                            0
                            0   0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9   1                  0.001     0.01      0.1         1    10   100
                                        Agonist Conc (nM)                                                 Agonist Conc (nM)
   DRUGS BEHAVIOR IN THE
PRESENCE OF SPARE RECEPTORS
            • AGONISTS
     APPARENT HIGHER POTENCY
    • COMPETITIVE ANTAGONISTS
      APPARENT LOWER POTENCY
 • NON-COMPETITIVE ANTAGONISTS
   APPARENTLY COMPETITIVE, UNTIL
    HIGHER CONCENTRATIONS ARE
              REACHED
        • PARTIAL AGONISTS
 HIGHER EFFICACY-> FULL AGONISTS
      PHYSIOLOGY OF SPARE
          RECEPTORS
• THE HIGHER THE RECEPTOR RESERVE IN A
  GIVEN TISSUE, THE MORE RESPONSIVE IT IS
           TO THE NATURAL AGONIST
        (APPARENT HIGHER POTENCY)
    • AT THE SAME CONCENTRATIONS OF
   HORMONE OR TRANSMITTER, DIFFERENT
       TISSUES WILL EXHIBIT DIFFERENT
      RESPONSIVENESS, BASED ON THEIR
             RECEPTOR RESERVE
 (DIFFERENTIAL CONTRACTION OF VARIOUS
               VASCULAR BEDS)
              EXAMPLES
• GRAVE’S DISEASE (HYPERTHYROIDISM,
  THYROTOXICOSIS) PRODUCTION OF ACTIVATING
  AUTO-ANTIBODIES AGAINST THYROID TSH
  RECEPTOR (HIGH T3/T4, LOW TSH)
• SYMPTOMS
  TACHYCARDIA, TACHYARRYTHMIAS
  INCREASED BMR (WEIGHT LOSS)
  LIMB TREMOR
  ANXIETY/NERVOUSNESS
  HEAT INTOLERANCE
  CAUSE T3/T4-INDUCED INCREASED SYNTHESIS
  AND DENSITY OF BETA-ADRENERGIC RECEPTORS
            EXAMPLES
GRAVE’S DISEASE – TREATMENT

INITIAL SYMPTOMATIC – BETA BLOCKERS
(PROPRANOLOL)
INTERMEDIATE – IODINE FIXATION
INHIBITORS
(PROPYLTHIOURACIL)
RADICAL – THYROID RADIOTHERAPY (131I)
OR SURGERY
            EXAMPLES
• HYPOTHYROIDISM DECREASED
  PRODUCTION T3/T4, HIGH TSH
• SYMPTOMS
  BRADYCARDIA
  DECREASED BMR (WEIGHT GAIN)
  APATHY
  COLD INTOLERANCE
  CAUSE DECREASED SYNTHESIS AND
  DENSITY OF BETA-ADRENERGIC
  RECEPTORS
  TREATMENT - TYROXIN
            EXAMPLES
MYASTHENIA GRAVIS - PRODUCTION OF AUTO-
ANTIBODIES AGAINST SKELETAL MUSCLE
CHOLINERGIC-NICOTINIC RECEPTORS
SYMPTOMS
MUSCULAR WEAKNESS, ESPECIALLY TO
REPEATED EFFORT
LIGHT – EYELIDS
GRAVE - RESPIRATORY
CAUSE - Ab-INDUCED INCREASED
INTERNALIZATION AND DECREASED DENSITY OF
NICOTINIC RECEPTORS, LEADING TO
HYPORESPONSIVENES TO RELEASED ACh AT NMJ
TREATMENT – AChE INHIBITORS
           EXAMPLES
HIGHLY IONIZED DRUGS
(PIRYDOSTYGMINE, NEOSTYGMINE,
AMBENONIUM, TO MINIMIZE CNS SIDE-
EFFECTS) ELEVATE Ach AT NMJ. HIGHER
PROPORTION OF RECEPTORS IS
OCCUPIED. WITH SUFFICIENT RECEPTOR
RESERVE, ENOUGH RECEPTORS ARE
ACTIVATED TO PRODUCE SUFFICIENT END-
PLATE POTENTIAL->ACTION POTENTIAL-
>FULL CONTRACTION

TUBOCURARINE, EDROPHONIUM FOR
DIAGNOSIS AND DOSE TITRATION
CONSTITUTIVE SIGNALING
     CONSTITUTIVELY ACTIVE
         RECEPTORS
RECEPTORS THAT DISPLAY MEASURABLE ACTIVITY
IN THE ABSENCE OF AN AGONIST
INITIALLY DISCOVERED BY MUTATING CERTAIN
DOMAINS IN GPCRs
SUBSEQUENTLY SHOWN TO CAUSE HUMAN
PATHOLOGIES
USING SENSITIVE TECHNOLOGY (LUCIFERASE
REPORTER) ALMOST ALL RECEPTORS DISPLAY
SOME DEGREE OF CONSTITUTIVE SIGNALING
THIS IS PREDICTED FROM A SIMPLE BINARY OR
TERTIARY RECEPTOR–LIGAND MODEL
Shenker A. Laue L. Kosugi S. Merendino JJ Jr. Minegishi T. Cutler GB Jr. A
constitutively activating mutation of the luteinizing hormone receptor in familial
male precocious puberty Nature. 365(6447):652-4, 1993.




Familial male precocious puberty (FMPP) is a gonadotropin-independent
disorder that is inherited in an autosomal dominant, male-limited pattern.
Affected males generally exhibit signs of puberty by age 4. Testosterone
production and Leydig cell hyperplasia occur in the context of prepubertal levels
of luteinizing hormone (LH). The LH receptor is a member of the family of G-
protein-coupled receptors, and we hypothesized that FMPP might be due to a
mutant receptor that is activated in the presence of little or no agonist. A single
A-->G base change that results in substitution of glycine for aspartate at
position 578 in the sixth transmembrane helix of the LH receptor was found in
affected individuals from eight different families. Linkage of the mutation to
FMPP was supported by restriction-digest analysis. COS-7 cells expressing the
mutant LH receptor exhibited markedly increased cyclic AMP production in the
absence of agonist, suggesting that autonomous Leydig cell activity in FMPP is
caused by a constitutively activated LH receptor.
Parma J. Duprez L. Van Sande J. Cochaux P. Gervy C. Mockel J. Dumont J.
Vassart G. Somatic mutations in the thyrotropin receptor gene cause
hyperfunctioning thyroid adenomas Nature. 365(6447):649-51.
 The pituitary hormone thyrotropin stimulates the function, expression of
 differentiation and growth of thyrocytes by cyclic AMP-dependent
 mechanisms. Tissue hyperplasia and hyperthyroidism are therefore expected
 to result when activation of the adenylyl cyclase-cAMP cascade is
 unregulated. This is observed in several situations, including when somatic
 mutations impair the GTPase activity of the G protein Gsa (ref 6, 7). Such a
 mechanism is probably responsible for the development of a minority of
 monoclonal hyperfunctioning thyroid adenomas. Here we identify somatic
 mutations in the carboxy-terminal portion of the third cytoplasmic loop of the
 thyrotropin receptor in three out of eleven hyperfunctioning thyroid adenomas.
 These mutations are restricted to tumour tissue and involve two different
 residues (aspartic acid at position 619 to glycine in two cases, and alanine at
 position 623 to isoleucine in one case). The mutant receptors confer
 constitutive activation of adenylyl cyclase when tested by transfection in COS
 cells. This shows that G-protein-coupled receptors are susceptible to
 constitutive activation by spontaneous somatic mutations and may thus
 behave as proto-oncogenes.
     CONSTITUTIVELY ACTIVE
    RECEPTORS-PREDICTIONS
CONSTITUTIVE SIGNALING MAY LEAD TO
PERSISTENT DESENSITIZATION
CLINICALLY, CONSTITUTIVELY ACTIVE MUTATION
MAY LEAD TO APPARENT LOWER RATHER THAN
HIGHER ACTIVITY
TREATING THIS APPARENT HYPO-ACTIVITY WITH
AGONISTS MAY LEAD TO MORE DESENSITIZATION
INVERSE AGONISTS INHIBIT CONSTITUTIVE ACTIVITY
AND MAY LEAD TO RECEPTOR RE-SENSITIZATION
ALL THIS PREDICTS THAT CONSTITUTIVE SIGNALING
MAY LEAD TO PARADOXICAL DRUG RESPONSES, I.E.
IDIOSYNCRATIC RESPONSES
     CONSTITUTIVELY ACTIVE
     RECEPTORS - EXAMPLE
RARE TUMORS, KAPOSI SARCOMA AND TISSUE
CAVITY PRIMARY LYMPHOMA EXHIBIT HIGH
INCIDENCE IN IMMUNODEFICIENCY (AIDS,
TRANSPLANTATIONS, CHEMOTHERAPY)
TUMOR CELLS’ GENOME CONTAINS THE ENTIRE
HUMAN HERPESVIRUS 8 GENOME
THE HUMAN HERPESVIRUS 8 GENOME CONTAINS A
SEQUENCE CODING FOR A GPCR-LIKE PROTEIN
(ORF74)
THIS PUTATIVE RECEPTOR (KSHV-GPCR) EXHIBITS
HOMOLOGY TO HUMAN IL-8 RECEPTOR – BEST
AGONIST GRO-ALPHA
WHEN EXPRESSED IN MODEL SYSTEMS, KSHV-GPCR
EXHIBITS PRONOUNCED CONSTITUTIVE ACTIVITY
      CONSTITUTIVELY ACTIVE
      RECEPTORS - EXAMPLE
CELLS EXPRESSNG KSHV-GPCR EXHIBIT MUCH
FASTER PROLIFERATION
WHEN INJECTED INTO NUDE MICE, THE ANIMALS
DEVELOP TUMORS SIMILAR TO KAPOSI SARCOMA
TRANSGENIC ANIMALS THAT EXPRESS KSHV-GPCR
IN ENDOTHELIAL TISSUE DEVELOP KS-LIKE TUMORS
CONCLUSION-CONSTITUTIVELY SIGNALING KSHV-
GPCR APPEARS TO BE A SUFFICIENT CAUSE OF
HUMAN MALIGNANCIES THAT DEVELOP IN
IMMUNODEFICIENT PATIENTS
CONSTITUTIVE SIGNALING OF KSHV-GPCR CAN BE
INHIBITED BY AN INVERSE AGONIST – INTERFERON –
INDUCED PROTEIN 10 (IP-10) – A 77kD MAMMALIAN
CYTOKINE
    CONSTITUTIVELY ACTIVE
    RECEPTORS - EXAMPLE
IP-10 IS A PUTATIVE DRUG FOR THE
TREATMENT OF KAPOSI SARCOMA OR
PRIMARY, TISSUE CAVITY LYMPHOMA

								
To top